ID ADT1_HUMAN Reviewed; 298 AA. AC P12235; D3DP59; DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2007, sequence version 4. DT 28-JAN-2026, entry version 253. DE RecName: Full=ADP/ATP translocase 1 {ECO:0000305}; DE AltName: Full=ADP,ATP carrier protein 1 {ECO:0000250|UniProtKB:P48962}; DE AltName: Full=ADP,ATP carrier protein, heart/skeletal muscle isoform T1 {ECO:0000303|PubMed:2541251}; DE AltName: Full=Adenine nucleotide translocator 1 {ECO:0000303|PubMed:2823266}; DE Short=ANT 1 {ECO:0000303|PubMed:2823266}; DE AltName: Full=Solute carrier family 25 member 4 {ECO:0000305}; GN Name=SLC25A4 {ECO:0000303|PubMed:25732997, ECO:0000312|HGNC:HGNC:10990}; GN Synonyms=AAC1 {ECO:0000250|UniProtKB:P48962}, GN ANT1 {ECO:0000303|PubMed:2823266}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=2823266; DOI=10.1073/pnas.84.21.7580; RA Neckelmann N., Li K., Wade R.P., Shuster R., Wallace D.C.; RT "cDNA sequence of a human skeletal muscle ADP/ATP translocator: lack of a RT leader peptide, divergence from a fibroblast translocator cDNA, and RT coevolution with mitochondrial DNA genes."; RL Proc. Natl. Acad. Sci. U.S.A. 84:7580-7584(1987). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=2541251; DOI=10.1016/0022-2836(89)90477-4; RA Cozens A.L., Runswick M.J., Walker J.E.; RT "DNA sequences of two expressed nuclear genes for human mitochondrial RT ADP/ATP translocase."; RL J. Mol. Biol. 206:261-280(1989). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2547778; DOI=10.1016/s0021-9258(18)71632-3; RA Li K., Warner C.K., Hodge J.A., Minoshima S., Kudoh J., Fukuyama R., RA Maekawa M., Shimizu Y., Shimizu N., Wallace D.C.; RT "A human muscle adenine nucleotide translocator gene has four exons, is RT located on chromosome 4, and is differentially expressed."; RL J. Biol. Chem. 264:13998-14004(1989). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=20843780; DOI=10.1093/nar/gkq750; RA Wang W., Shen P., Thiyagarajan S., Lin S., Palm C., Horvath R., RA Klopstock T., Cutler D., Pique L., Schrijver I., Davis R.W., Mindrinos M., RA Speed T.P., Scharfe C.; RT "Identification of rare DNA variants in mitochondrial disorders with RT improved array-based sequencing."; RL Nucleic Acids Res. 39:44-58(2011). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Eye, Mammary gland, and PNS; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-37. RC TISSUE=Liver; RX PubMed=2829183; DOI=10.1073/pnas.85.2.377; RA Houldsworth J., Attardi G.; RT "Two distinct genes for ADP/ATP translocase are expressed at the mRNA level RT in adult human liver."; RL Proc. Natl. Acad. Sci. U.S.A. 85:377-381(1988). RN [8] RP PROTEIN SEQUENCE OF 2-31; 34-43; 64-92; 141-147; 189-199 AND 273-296, RP CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT GLY-2, AND IDENTIFICATION RP BY MASS SPECTROMETRY. RC TISSUE=B-cell lymphoma; RA Bienvenut W.V.; RL Submitted (OCT-2004) to UniProtKB. RN [9] RP INTERACTION WITH HIV-1 VPR (MICROBIAL INFECTION). RX PubMed=16120388; DOI=10.1016/j.mito.2004.06.012; RA Deniaud A., Brenner C., Kroemer G.; RT "Mitochondrial membrane permeabilization by HIV-1 Vpr."; RL Mitochondrion 4:223-233(2004). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [12] RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION, RP AND CHARACTERIZATION OF VARIANTS PEOA2 PRO-114 AND MET-289. RX PubMed=21586654; DOI=10.1093/hmg/ddr200; RA Kawamata H., Tiranti V., Magrane J., Chinopoulos C., Manfredi G.; RT "adPEO mutations in ANT1 impair ADP-ATP translocation in muscle RT mitochondria."; RL Hum. Mol. Genet. 20:2964-2974(2011). RN [13] RP INVOLVEMENT IN MTDPS12B. RX PubMed=22187496; DOI=10.1136/jmedgenet-2011-100504; RA Echaniz-Laguna A., Chassagne M., Ceresuela J., Rouvet I., Padet S., RA Acquaviva C., Nataf S., Vinzio S., Bozon D., Mousson de Camaret B.; RT "Complete loss of expression of the ANT1 gene causing cardiomyopathy and RT myopathy."; RL J. Med. Genet. 49:146-150(2012). RN [14] RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, AND BIOPHYSICOCHEMICAL RP PROPERTIES. RX PubMed=23173940; DOI=10.3109/09687688.2012.745175; RA Mifsud J., Ravaud S., Krammer E.M., Chipot C., Kunji E.R., RA Pebay-Peyroula E., Dehez F.; RT "The substrate specificity of the human ADP/ATP carrier AAC1."; RL Mol. Membr. Biol. 30:160-168(2013). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [16] RP FUNCTION, INVOLVEMENT IN MTDPS12A, VARIANTS MTDPS12A HIS-80 AND GLY-235, RP CHARACTERIZATION OF VARIANTS MTDPS12A HIS-80 AND GLY-235, CHARACTERIZATION RP OF VARIANTS PEOA2 ASP-90; PRO-98; GLY-104 AND PRO-114, AND CHARACTERIZATION RP OF VARIANTS MTDPS12B ASP-123 AND PRO-236. RX PubMed=27693233; DOI=10.1016/j.ajhg.2016.08.014; RA Thompson K., Majd H., Dallabona C., Reinson K., King M.S., Alston C.L., RA He L., Lodi T., Jones S.A., Fattal-Valevski A., Fraenkel N.D., Saada A., RA Haham A., Isohanni P., Vara R., Barbosa I.A., Simpson M.A., Deshpande C., RA Puusepp S., Bonnen P.E., Rodenburg R.J., Suomalainen A., Ounap K., RA Elpeleg O., Ferrero I., McFarland R., Kunji E.R., Taylor R.W.; RT "Recurrent de novo dominant mutations in SLC25A4 cause severe early-onset RT mitochondrial disease and loss of mitochondrial DNA copy number."; RL Am. J. Hum. Genet. 99:860-876(2016). RN [17] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RX PubMed=27641616; DOI=10.1038/srep33516; RA Marginedas-Freixa I., Hattab C., Bouyer G., Halle F., Chene A., RA Lefevre S.D., Cambot M., Cueff A., Schmitt M., Gamain B., Lacapere J.J., RA Egee S., Bihel F., Le Van Kim C., Ostuni M.A.; RT "TSPO ligands stimulate ZnPPIX transport and ROS accumulation leading to RT the inhibition of P. falciparum growth in human blood."; RL Sci. Rep. 6:33516-33516(2016). RN [18] RP FUNCTION, AND INTERACTION WITH ARHGAP11B. RX PubMed=31883789; DOI=10.1016/j.neuron.2019.11.027; RA Namba T., Doczi J., Pinson A., Xing L., Kalebic N., Wilsch-Braeuninger M., RA Long K.R., Vaid S., Lauer J., Bogdanova A., Borgonovo B., Shevchenko A., RA Keller P., Drechsel D., Kurzchalia T., Wimberger P., Chinopoulos C., RA Huttner W.B.; RT "Human-specific ARHGAP11B acts in mitochondria to expand neocortical RT progenitors by glutaminolysis."; RL Neuron 105:867-881(2020). RN [19] RP FUNCTION. RX PubMed=37278158; DOI=10.15252/embr.202357127; RA Cimadamore-Werthein C., Jaiquel Baron S., King M.S., Springett R., RA Kunji E.R.; RT "Human mitochondrial ADP/ATP carrier SLC25A4 operates with a ping-pong RT kinetic mechanism."; RL EMBO Rep. 24:e57127-e57127(2023). RN [20] RP VARIANTS PEOA2 PRO-114 AND MET-289. RX PubMed=10926541; DOI=10.1126/science.289.5480.782; RA Kaukonen J., Juselius J.K., Tiranti V., Kyttala A., Zeviani M., Comi G.P., RA Keranen J., Peltonen L., Suomalainen A.; RT "Role of adenine nucleotide translocator 1 in mtDNA maintenance."; RL Science 289:782-785(2000). RN [21] RP VARIANT PEOA2 PRO-98. RX PubMed=11756613; DOI=10.1212/wnl.57.12.2295; RA Napoli L., Bordoni A., Zeviani M., Hadjigeorgiou G.M., Sciacco M., RA Tiranti V., Terentiou A., Moggio M., Papadimitriou A., Scarlato G., RA Comi G.P.; RT "A novel missense adenine nucleotide translocator-1 gene mutation in a RT Greek adPEO family."; RL Neurology 57:2295-2298(2001). RN [22] RP VARIANT PEOA2 GLY-104. RX PubMed=12112115; DOI=10.1002/ana.10172; RA Komaki H., Fukazawa T., Houzen H., Yoshida K., Nonaka I., Goto Y.; RT "A novel D104G mutation in the adenine nucleotide translocator 1 gene in RT autosomal dominant progressive external ophthalmoplegia patients with RT mitochondrial DNA with multiple deletions."; RL Ann. Neurol. 51:645-648(2002). RN [23] RP VARIANT PEOA2 MET-289. RX PubMed=12707443; DOI=10.1212/01.wnl.0000056088.09408.3c; RA Agostino A., Valletta L., Chinnery P.F., Ferrari G., Carrara F., RA Taylor R.W., Schaefer A.M., Turnbull D.M., Tiranti V., Zeviani M.; RT "Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external RT ophthalmoplegia (PEO)."; RL Neurology 60:1354-1356(2003). RN [24] RP VARIANT MTDPS12B ASP-123. RX PubMed=16155110; DOI=10.1093/hmg/ddi341; RA Palmieri L., Alberio S., Pisano I., Lodi T., Meznaric-Petrusa M., Zidar J., RA Santoro A., Scarcia P., Fontanesi F., Lamantea E., Ferrero I., Zeviani M.; RT "Complete loss-of-function of the heart/muscle-specific adenine nucleotide RT translocator is associated with mitochondrial myopathy and RT cardiomyopathy."; RL Hum. Mol. Genet. 14:3079-3088(2005). RN [25] RP VARIANT PEOA2 ASP-90. RX PubMed=15792871; DOI=10.1016/j.nmd.2004.12.004; RA Deschauer M., Hudson G., Mueller T., Taylor R.W., Chinnery P.F., Zierz S.; RT "A novel ANT1 gene mutation with probable germline mosaicism in autosomal RT dominant progressive external ophthalmoplegia."; RL Neuromuscul. Disord. 15:311-315(2005). RN [26] RP VARIANTS PEOA2 PRO-98 AND PRO-114. RX PubMed=18575922; DOI=10.1007/s00415-008-0926-3; RA Virgilio R., Ronchi D., Hadjigeorgiou G.M., Bordoni A., Saladino F., RA Moggio M., Adobbati L., Kafetsouli D., Tsironi E., Previtali S., RA Papadimitriou A., Bresolin N., Comi G.P.; RT "Novel Twinkle (PEO1) gene mutations in Mendelian progressive external RT ophthalmoplegia."; RL J. Neurol. 255:1384-1391(2008). RN [27] RP VARIANT MTDPS12B PRO-236. RX PubMed=25732997; DOI=10.1007/8904_2015_409; RA Koerver-Keularts I.M., de Visser M., Bakker H.D., Wanders R.J., RA Vansenne F., Scholte H.R., Dorland L., Nicolaes G.A., Spaapen L.M., RA Smeets H.J., Hendrickx A.T., van den Bosch B.J.; RT "Two novel mutations in the SLC25A4 gene in a patient with mitochondrial RT myopathy."; RL JIMD Rep. 22:39-45(2015). RN [28] RP VARIANT GLN-33, CHARACTERIZATION OF VARIANT GLN-33, AND FUNCTION. RX PubMed=30046662; DOI=10.1212/nxg.0000000000000256; RA King M.S., Thompson K., Hopton S., He L., Kunji E.R.S., Taylor R.W., RA Ortiz-Gonzalez X.R.; RT "Expanding the phenotype of de novo SLC25A4-linked mitochondrial disease to RT include mild myopathy."; RL Neurol. Genet. 4:e256-e256(2018). CC -!- FUNCTION: ADP:ATP antiporter that mediates import of ADP into the CC mitochondrial matrix for ATP synthesis, and export of ATP out to fuel CC the cell (PubMed:21586654, PubMed:27693233, PubMed:23173940, CC PubMed:30046662). Cycles between the cytoplasmic-open state (c-state) CC and the matrix-open state (m-state): operates by the alternating access CC mechanism with a single substrate-binding site intermittently exposed CC to either the cytosolic (c-state) or matrix (m-state) side of the inner CC mitochondrial membrane (By similarity). Substrate exchange across the CC membrane occurs consecutively with one substrate being transported CC first, then dissociating from the substrate binding site before the CC second substrate binds for transport in the opposite direction CC (PubMed:37278158). In addition to its ADP:ATP antiporter activity, also CC involved in mitochondrial uncoupling and mitochondrial permeability CC transition pore (mPTP) activity (PubMed:31883789). Plays a role in CC mitochondrial uncoupling by acting as a proton transporter: proton CC transport uncouples the proton flows via the electron transport chain CC and ATP synthase to reduce the efficiency of ATP production and cause CC mitochondrial thermogenesis (By similarity). Proton transporter CC activity is inhibited by ADP:ATP antiporter activity, suggesting that CC SLC25A4/ANT1 acts as a master regulator of mitochondrial energy output CC by maintaining a delicate balance between ATP production (ADP:ATP CC antiporter activity) and thermogenesis (proton transporter activity) CC (By similarity). Proton transporter activity requires free fatty acids CC as cofactor, but does not transport it (By similarity). Also plays a CC key role in mPTP opening, a non-specific pore that enables free passage CC of the mitochondrial membranes to solutes of up to 1.5 kDa, and which CC contributes to cell death (PubMed:31883789). It is however unclear if CC SLC25A4/ANT1 constitutes a pore-forming component of mPTP or regulates CC it (By similarity). Acts as a regulator of mitophagy independently of CC ADP:ATP antiporter activity: promotes mitophagy via interaction with CC TIMM44, leading to inhibit the presequence translocase TIMM23, thereby CC promoting stabilization of PINK1 (By similarity). CC {ECO:0000250|UniProtKB:G2QNH0, ECO:0000250|UniProtKB:P48962, CC ECO:0000269|PubMed:21586654, ECO:0000269|PubMed:23173940, CC ECO:0000269|PubMed:27693233, ECO:0000269|PubMed:31883789, CC ECO:0000269|PubMed:37278158}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ADP(in) + ATP(out) = ADP(out) + ATP(in); Xref=Rhea:RHEA:34999, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:456216; CC Evidence={ECO:0000269|PubMed:21586654, ECO:0000269|PubMed:23173940}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H(+)(in) = H(+)(out); Xref=Rhea:RHEA:34979, ChEBI:CHEBI:15378; CC Evidence={ECO:0000250|UniProtKB:P48962}; CC -!- ACTIVITY REGULATION: The matrix-open state (m-state) is inhibited by CC the membrane-permeable bongkrekic acid (BKA) PubMed:23173940. The CC cytoplasmic-open state (c-state) is inhibited by the membrane- CC impermeable toxic inhibitor carboxyatractyloside (CATR) CC (PubMed:21586654, PubMed:23173940). Proton transporter activity is CC inhibited by ADP:ATP antiporter activity (By similarity). CC {ECO:0000250|UniProtKB:G2QNH0, ECO:0000250|UniProtKB:P48962, CC ECO:0000269|PubMed:21586654}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=23.7 uM for ATP {ECO:0000269|PubMed:23173940}; CC Vmax=14.6 nmol/min/mg enzyme for ATP uptake CC {ECO:0000269|PubMed:23173940}; CC -!- SUBUNIT: Monomer (By similarity). Found in a complex with ARL2, ARL2BP CC and SLC25A4/ANT1 (By similarity). Interacts with ARL2BP (By CC similarity). Interacts with ARHGAP11B, thereby inhibiting the CC mitochondrial permeability transition pore (mPTP) (PubMed:31883789). CC Interacts with TIMM44; leading to inhibit the presequence translocase CC TIMM23, thereby promoting stabilization of PINK1 (By similarity). CC {ECO:0000250|UniProtKB:G2QNH0, ECO:0000250|UniProtKB:P02722, CC ECO:0000250|UniProtKB:P48962, ECO:0000269|PubMed:31883789}. CC -!- SUBUNIT: (Microbial infection) Interacts with HIV-1 Vpr. CC {ECO:0000269|PubMed:16120388}. CC -!- INTERACTION: CC P12235; Q5S007: LRRK2; NbExp=2; IntAct=EBI-359074, EBI-5323863; CC P12235; P22736-1: NR4A1; NbExp=2; IntAct=EBI-359074, EBI-16085263; CC P12235; P12236: SLC25A6; NbExp=2; IntAct=EBI-359074, EBI-356254; CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane CC {ECO:0000269|PubMed:21586654}; Multi-pass membrane protein CC {ECO:0000255}. Membrane {ECO:0000269|PubMed:27641616}; Multi-pass CC membrane protein {ECO:0000255}. Note=The complex formed with ARL2BP, CC ARL2 and SLC25A4/ANT1 is expressed in mitochondria (By similarity). May CC localize to non-mitochondrial membranes (PubMed:27641616). CC {ECO:0000250|UniProtKB:P48962, ECO:0000269|PubMed:27641616}. CC -!- TISSUE SPECIFICITY: Expressed in erythrocytes (at protein level). CC {ECO:0000269|PubMed:27641616}. CC -!- DOMAIN: The transmembrane helices are not perpendicular to the plane of CC the membrane, but cross the membrane at an angle. Odd-numbered CC transmembrane helices exhibit a sharp kink, due to the presence of a CC conserved proline residue. {ECO:0000250|UniProtKB:P02722}. CC -!- PTM: Under cell death induction, transglutaminated by TGM2. CC Transglutamination leads to formation of covalent cross-links between a CC glutamine and the epsilon-amino group of a lysine residue, forming CC polymers. {ECO:0000250|UniProtKB:P48962}. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 2 (PEOA2) [MIM:609283]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:10926541, CC ECO:0000269|PubMed:11756613, ECO:0000269|PubMed:12112115, CC ECO:0000269|PubMed:12707443, ECO:0000269|PubMed:15792871, CC ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:21586654, CC ECO:0000269|PubMed:27693233}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 12B, cardiomyopathic type CC (MTDPS12B) [MIM:615418]: An autosomal recessive mitochondrial disorder CC characterized by childhood onset of slowly progressive hypertrophic CC cardiomyopathy and generalized skeletal myopathy resulting in exercise CC intolerance and, in some patients, muscle weakness and atrophy. CC Skeletal muscle biopsy shows ragged red fibers, mtDNA depletion, and CC accumulation of abnormal mitochondria. {ECO:0000269|PubMed:16155110, CC ECO:0000269|PubMed:22187496, ECO:0000269|PubMed:25732997, CC ECO:0000269|PubMed:27693233}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 12A, cardiomyopathic type CC (MTDPS12A) [MIM:617184]: An autosomal dominant mitochondrial disorder CC characterized by severe hypotonia due to mitochondrial dysfunction CC apparent at birth. Affected infants have respiratory insufficiency CC requiring mechanical ventilation and have poor or no motor development. CC Many die in infancy, and those that survive have profound hypotonia CC with significant muscle weakness and inability to walk independently. CC Some patients develop hypertrophic cardiomyopathy. Muscle samples show CC mtDNA depletion and severe combined mitochondrial respiratory chain CC deficiencies. {ECO:0000269|PubMed:27693233}. Note=The disease is caused CC by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the mitochondrial carrier (TC 2.A.29) family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; J02966; AAA61223.1; -; mRNA. DR EMBL; J04982; AAA51736.1; -; Genomic_DNA. DR EMBL; HQ206346; ADP92294.1; -; Genomic_DNA. DR EMBL; HQ206347; ADP92295.1; -; Genomic_DNA. DR EMBL; HQ206348; ADP92296.1; -; Genomic_DNA. DR EMBL; HQ206349; ADP92297.1; -; Genomic_DNA. DR EMBL; HQ206350; ADP92298.1; -; Genomic_DNA. DR EMBL; HQ206351; ADP92299.1; -; Genomic_DNA. DR EMBL; HQ206352; ADP92300.1; -; Genomic_DNA. DR EMBL; HQ206353; ADP92301.1; -; Genomic_DNA. DR EMBL; HQ206354; ADP92302.1; -; Genomic_DNA. DR EMBL; HQ206355; ADP92303.1; -; Genomic_DNA. DR EMBL; HQ206356; ADP92304.1; -; Genomic_DNA. DR EMBL; HQ206357; ADP92305.1; -; Genomic_DNA. DR EMBL; HQ206358; ADP92306.1; -; Genomic_DNA. DR EMBL; HQ206359; ADP92307.1; -; Genomic_DNA. DR EMBL; HQ206360; ADP92308.1; -; Genomic_DNA. DR EMBL; HQ206361; ADP92309.1; -; Genomic_DNA. DR EMBL; HQ206362; ADP92310.1; -; Genomic_DNA. DR EMBL; HQ206363; ADP92311.1; -; Genomic_DNA. DR EMBL; HQ206364; ADP92312.1; -; Genomic_DNA. DR EMBL; HQ206365; ADP92313.1; -; Genomic_DNA. DR EMBL; HQ206366; ADP92314.1; -; Genomic_DNA. DR EMBL; HQ206367; ADP92315.1; -; Genomic_DNA. DR EMBL; HQ206368; ADP92316.1; -; Genomic_DNA. DR EMBL; HQ206369; ADP92317.1; -; Genomic_DNA. DR EMBL; HQ206370; ADP92318.1; -; Genomic_DNA. DR EMBL; HQ206371; ADP92319.1; -; Genomic_DNA. DR EMBL; HQ206372; ADP92320.1; -; Genomic_DNA. DR EMBL; HQ206373; ADP92321.1; -; Genomic_DNA. DR EMBL; HQ206374; ADP92322.1; -; Genomic_DNA. DR EMBL; HQ206375; ADP92323.1; -; Genomic_DNA. DR EMBL; HQ206376; ADP92324.1; -; Genomic_DNA. DR EMBL; HQ206377; ADP92325.1; -; Genomic_DNA. DR EMBL; HQ206378; ADP92326.1; -; Genomic_DNA. DR EMBL; HQ206379; ADP92327.1; -; Genomic_DNA. DR EMBL; HQ206380; ADP92328.1; -; Genomic_DNA. DR EMBL; HQ206381; ADP92329.1; -; Genomic_DNA. DR EMBL; HQ206382; ADP92330.1; -; Genomic_DNA. DR EMBL; HQ206383; ADP92331.1; -; Genomic_DNA. DR EMBL; HQ206384; ADP92332.1; -; Genomic_DNA. DR EMBL; HQ206385; ADP92333.1; -; Genomic_DNA. DR EMBL; CH471056; EAX04655.1; -; Genomic_DNA. DR EMBL; CH471056; EAX04656.1; -; Genomic_DNA. DR EMBL; BC008664; AAH08664.1; -; mRNA. DR EMBL; BC061589; AAH61589.1; -; mRNA. DR EMBL; BC063643; AAH63643.1; -; mRNA. DR EMBL; J03593; AAA36751.1; -; mRNA. DR CCDS; CCDS34114.1; -. DR PIR; A44778; A44778. DR RefSeq; NP_001142.2; NM_001151.4. DR AlphaFoldDB; P12235; -. DR SMR; P12235; -. DR BioGRID; 106788; 352. DR DIP; DIP-33116N; -. DR FunCoup; P12235; 1978. DR IntAct; P12235; 125. DR MINT; P12235; -. DR STRING; 9606.ENSP00000281456; -. DR DrugBank; DB01736; [3-(Dodecanoylamino)Propyl](Hydroxy)Dimethylammonium. DR DrugBank; DB00171; ATP. DR DrugBank; DB02426; Carboxyatractyloside. DR DrugBank; DB00720; Clodronic acid. DR DrugBank; DB04178; Di-Stearoyl-3-Sn-Phosphatidylcholine. DR DrugBank; DB01077; Etidronic acid. DR DrugBank; DB03429; Tetrastearoyl cardiolipin. DR DrugCentral; P12235; -. DR MoonProt; P12235; -. DR TCDB; 2.A.29.1.2; the mitochondrial carrier (mc) family. DR GlyGen; P12235; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P12235; -. DR MetOSite; P12235; -. DR PhosphoSitePlus; P12235; -. DR SwissPalm; P12235; -. DR BioMuta; SLC25A4; -. DR DMDM; 113455; -. DR jPOST; P12235; -. DR MassIVE; P12235; -. DR PaxDb; 9606-ENSP00000281456; -. DR PeptideAtlas; P12235; -. DR ProteomicsDB; 52836; -. DR Pumba; P12235; -. DR TopDownProteomics; P12235; -. DR Antibodypedia; 28911; 156 antibodies from 24 providers. DR DNASU; 291; -. DR Ensembl; ENST00000281456.11; ENSP00000281456.5; ENSG00000151729.12. DR GeneID; 291; -. DR KEGG; hsa:291; -. DR MANE-Select; ENST00000281456.11; ENSP00000281456.5; NM_001151.4; NP_001142.2. DR UCSC; uc003ixd.4; human. DR AGR; HGNC:10990; -. DR ClinPGx; PA35866; -. DR CTD; 291; -. DR DisGeNET; 291; -. DR GeneCards; SLC25A4; -. DR HGNC; HGNC:10990; SLC25A4. DR HPA; ENSG00000151729; Group enriched (heart muscle, skeletal muscle, tongue). DR MalaCards; SLC25A4; -. DR MIM; 103220; gene. DR MIM; 609283; phenotype. DR MIM; 615418; phenotype. DR MIM; 617184; phenotype. DR OpenTargets; ENSG00000151729; -. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR Orphanet; 1369; Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome. DR VEuPathDB; HostDB:ENSG00000151729; -. DR eggNOG; KOG0749; Eukaryota. DR GeneTree; ENSGT00940000154622; -. DR InParanoid; P12235; -. DR OMA; HPAMYQR; -. DR OrthoDB; 270584at2759; -. DR PAN-GO; P12235; 4 GO annotations based on evolutionary models. DR PhylomeDB; P12235; -. DR PathwayCommons; P12235; -. DR Reactome; R-HSA-1268020; Mitochondrial protein import. DR Reactome; R-HSA-166187; Mitochondrial Uncoupling. DR Reactome; R-HSA-180897; Vpr-mediated induction of apoptosis by mitochondrial outer membrane permeabilization. DR Reactome; R-HSA-83936; Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane. DR SignaLink; P12235; -. DR SIGNOR; P12235; -. DR Agora; ENSG00000151729; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 291; 14 hits in 1168 CRISPR screens. DR CD-CODE; 91857CE7; Nucleolus. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; SLC25A4; human. DR GeneWiki; SLC25A4; -. DR GenomeRNAi; 291; -. DR Pharos; P12235; Tbio. DR PRO; PR:P12235; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P12235; protein. DR Bgee; ENSG00000151729; Expressed in left ventricle myocardium and 209 other cell types or tissues. DR ExpressionAtlas; P12235; baseline and differential. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:UniProtKB. DR GO; GO:0031966; C:mitochondrial membrane; ISS:UniProtKB. DR GO; GO:0005757; C:mitochondrial permeability transition pore complex; ISS:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; TAS:ProtInc. DR GO; GO:0015207; F:adenine transmembrane transporter activity; TAS:ProtInc. DR GO; GO:0005471; F:ATP:ADP antiporter activity; IDA:UniProtKB. DR GO; GO:0017077; F:oxidative phosphorylation uncoupler activity; ISS:UniProtKB. DR GO; GO:0015078; F:proton transmembrane transporter activity; TAS:Reactome. DR GO; GO:1990845; P:adaptive thermogenesis; ISS:UniProtKB. DR GO; GO:0015866; P:ADP transport; IMP:UniProtKB. DR GO; GO:0008637; P:apoptotic mitochondrial changes; IEA:Ensembl. DR GO; GO:0006091; P:generation of precursor metabolites and energy; TAS:ProtInc. DR GO; GO:0140021; P:mitochondrial ADP transmembrane transport; IDA:UniProtKB. DR GO; GO:1990544; P:mitochondrial ATP transmembrane transport; IDA:UniProtKB. DR GO; GO:1901029; P:negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; IBA:GO_Central. DR GO; GO:0060546; P:negative regulation of necroptotic process; IMP:BHF-UCL. DR GO; GO:1901526; P:positive regulation of mitophagy; ISS:UniProtKB. DR GO; GO:0046902; P:regulation of mitochondrial membrane permeability; ISS:UniProtKB. DR FunFam; 1.50.40.10:FF:000002; Putative ADP/ATP translocase 2-like; 1. DR Gene3D; 1.50.40.10; Mitochondrial carrier domain; 1. DR InterPro; IPR002113; ADT_euk_type. DR InterPro; IPR002067; MCP. DR InterPro; IPR023395; MCP_dom_sf. DR InterPro; IPR018108; MCP_transmembrane. DR PANTHER; PTHR45635; ADP,ATP CARRIER PROTEIN 1-RELATED-RELATED; 1. DR PANTHER; PTHR45635:SF32; ADP_ATP TRANSLOCASE 1; 1. DR Pfam; PF00153; Mito_carr; 3. DR PRINTS; PR00927; ADPTRNSLCASE. DR PRINTS; PR00926; MITOCARRIER. DR SUPFAM; SSF103506; Mitochondrial carrier; 1. DR PROSITE; PS50920; SOLCAR; 3. PE 1: Evidence at protein level; KW Acetylation; Antiport; ATP-binding; Cardiomyopathy; KW Direct protein sequencing; Disease variant; Host-virus interaction; KW Membrane; Methylation; Mitochondrion; Mitochondrion inner membrane; KW Nucleotide-binding; Phosphoprotein; Primary mitochondrial disease; KW Progressive external ophthalmoplegia; Proteomics identification; KW Reference proteome; Repeat; S-nitrosylation; Transmembrane; KW Transmembrane helix; Transport. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|Ref.8" FT CHAIN 2..298 FT /note="ADP/ATP translocase 1" FT /id="PRO_0000090574" FT TOPO_DOM 2..7 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000305" FT TRANSMEM 8..37 FT /note="Helical; Name=1" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 38..74 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000305" FT TRANSMEM 75..99 FT /note="Helical; Name=2" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 100..109 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000305" FT TRANSMEM 110..130 FT /note="Helical; Name=3" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 131..178 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000305" FT TRANSMEM 179..199 FT /note="Helical; Name=4" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 200..210 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000305" FT TRANSMEM 211..231 FT /note="Helical; Name=5" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 232..273 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000305" FT TRANSMEM 274..291 FT /note="Helical; Name=6" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 292..298 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000305" FT REPEAT 6..98 FT /note="Solcar 1" FT REPEAT 111..201 FT /note="Solcar 2" FT REPEAT 212..297 FT /note="Solcar 3" FT REGION 235..240 FT /note="Important for transport activity" FT /evidence="ECO:0000269|PubMed:27693233" FT MOTIF 235..240 FT /note="Nucleotide carrier signature motif" FT /evidence="ECO:0000250|UniProtKB:P02722" FT BINDING 80 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:P02722" FT BINDING 92 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:P02722" FT BINDING 235 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:P02722" FT MOD_RES 2 FT /note="N-acetylglycine" FT /evidence="ECO:0000269|Ref.8" FT MOD_RES 7 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q05962" FT MOD_RES 52 FT /note="N6,N6,N6-trimethyllysine" FT /evidence="ECO:0000250|UniProtKB:Q05962" FT MOD_RES 147 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:P48962" FT MOD_RES 160 FT /note="S-nitrosocysteine" FT /evidence="ECO:0000250|UniProtKB:Q05962" FT MOD_RES 245 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:P48962" FT MOD_RES 272 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:P48962" FT VARIANT 33 FT /note="K -> Q (found in a patient with mild childhood-onset FT myopathy without evidence of other clinical features such FT as cardiomyopathy, encephalopathy or ophthalmoplegia; FT likely pathogenic; abolishes ADP transport)" FT /evidence="ECO:0000269|PubMed:30046662" FT /id="VAR_090742" FT VARIANT 80 FT /note="R -> H (in MTDPS12A; decreased function in ADP FT transport; dbSNP:rs886041081)" FT /evidence="ECO:0000269|PubMed:27693233" FT /id="VAR_078071" FT VARIANT 90 FT /note="A -> D (in PEOA2; decreased function in ADP FT transport)" FT /evidence="ECO:0000269|PubMed:15792871, FT ECO:0000269|PubMed:27693233" FT /id="VAR_038814" FT VARIANT 98 FT /note="L -> P (in PEOA2; decreased function in ADP FT transport; dbSNP:rs104893876)" FT /evidence="ECO:0000269|PubMed:11756613, FT ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:27693233" FT /id="VAR_022459" FT VARIANT 104 FT /note="D -> G (in PEOA2; decreased function in ADP FT transport; dbSNP:rs28999114)" FT /evidence="ECO:0000269|PubMed:12112115, FT ECO:0000269|PubMed:27693233" FT /id="VAR_022460" FT VARIANT 114 FT /note="A -> P (in PEOA2; decreased function in ADP FT transport; inverted direction of ADP:ATP transport, with FT ATP entering the mitochondrial matrix; dbSNP:rs104893873)" FT /evidence="ECO:0000269|PubMed:10926541, FT ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:21586654, FT ECO:0000269|PubMed:27693233" FT /id="VAR_012111" FT VARIANT 123 FT /note="A -> D (in MTDPS12B; loss of function in ADP FT transport; dbSNP:rs121912683)" FT /evidence="ECO:0000269|PubMed:16155110, FT ECO:0000269|PubMed:27693233" FT /id="VAR_038815" FT VARIANT 235 FT /note="R -> G (in MTDPS12A; severely decreased function in FT ADP transport; dbSNP:rs886041082)" FT /evidence="ECO:0000269|PubMed:27693233" FT /id="VAR_078072" FT VARIANT 236 FT /note="R -> P (in MTDPS12B; loss of function in ADP FT transport; dbSNP:rs770816416)" FT /evidence="ECO:0000269|PubMed:25732997, FT ECO:0000269|PubMed:27693233" FT /id="VAR_078073" FT VARIANT 289 FT /note="V -> M (in PEOA2; inverted direction of ADP:ATP FT transport, with ATP entering the mitochondrial matrix; FT dbSNP:rs104893874)" FT /evidence="ECO:0000269|PubMed:10926541, FT ECO:0000269|PubMed:12707443, ECO:0000269|PubMed:21586654" FT /id="VAR_012112" FT CONFLICT 16 FT /note="G -> A (in Ref. 1; AAA61223)" FT /evidence="ECO:0000305" FT CONFLICT 147..149 FT /note="KGA -> RR (in Ref. 1; AAA61223)" FT /evidence="ECO:0000305" FT CONFLICT 227 FT /note="V -> L (in Ref. 1; AAA61223)" FT /evidence="ECO:0000305" SQ SEQUENCE 298 AA; 33064 MW; 59F0DFAEC4E7CFBB CRC64; MGDHAWSFLK DFLAGGVAAA VSKTAVAPIE RVKLLLQVQH ASKQISAEKQ YKGIIDCVVR IPKEQGFLSF WRGNLANVIR YFPTQALNFA FKDKYKQLFL GGVDRHKQFW RYFAGNLASG GAAGATSLCF VYPLDFARTR LAADVGKGAA QREFHGLGDC IIKIFKSDGL RGLYQGFNVS VQGIIIYRAA YFGVYDTAKG MLPDPKNVHI FVSWMIAQSV TAVAGLVSYP FDTVRRRMMM QSGRKGADIM YTGTVDCWRK IAKDEGAKAF FKGAWSNVLR GMGGAFVLVL YDEIKKYV // ID ANGI_HUMAN Reviewed; 147 AA. AC P03950; Q05CV1; Q53X86; Q6P5T2; Q8WXE7; DT 23-OCT-1986, integrated into UniProtKB/Swiss-Prot. DT 23-OCT-1986, sequence version 1. DT 28-JAN-2026, entry version 253. DE RecName: Full=Angiogenin {ECO:0000303|PubMed:2866795}; DE EC=3.1.27.- {ECO:0000269|PubMed:1400510, ECO:0000269|PubMed:21855800, ECO:0000269|PubMed:2424496, ECO:0000269|PubMed:2459697, ECO:0000269|PubMed:28176817, ECO:0000269|PubMed:38718836}; DE AltName: Full=Ribonuclease 5; DE Short=RNase 5; DE Flags: Precursor; GN Name=ANG {ECO:0000303|PubMed:11919285, ECO:0000312|HGNC:HGNC:483}; GN Synonyms=RNASE5; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2866795; DOI=10.1021/bi00341a032; RA Kurachi K., Davie E.W., Strydom D.J., Riordan J.F., Vallee B.L.; RT "Sequence of the cDNA and gene for angiogenin, a human angiogenesis RT factor."; RL Biochemistry 24:5494-5499(1985). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLU-84. RX PubMed=11919285; DOI=10.1093/oxfordjournals.molbev.a004099; RA Zhang J., Rosenberg H.F.; RT "Diversifying selection of the tumor-growth promoter angiogenin in primate RT evolution."; RL Mol. Biol. Evol. 19:438-445(2002). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Li J., Wang H.; RL Submitted (SEP-2008) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Small intestine; RA Wakamatsu A., Yamamoto J., Kimura K., Kaida T., Tsuchiya K., Iida Y., RA Takayama Y., Murakawa K., Kanehori K., Andoh T., Kagawa N., Sato R., RA Kawamura Y., Tanaka S., Kisu Y., Sugano S., Goshima N., Nomura N., RA Isogai T.; RT "NEDO functional analysis of protein and research application project."; RL Submitted (JAN-2008) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Liver; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP PROTEIN SEQUENCE OF 25-147, PYROGLUTAMATE FORMATION AT GLN-25, AND RP DISULFIDE BONDS. RX PubMed=2866794; DOI=10.1021/bi00341a031; RA Strydom D.J., Fett J.W., Lobb R.R., Alderman E.M., Bethune J.L., RA Riordan J.F., Vallee B.L.; RT "Amino acid sequence of human tumor derived angiogenin."; RL Biochemistry 24:5486-5494(1985). RN [9] RP FUNCTION. RX PubMed=4074709; DOI=10.1021/bi00341a030; RA Fett J.W., Strydom D.J., Lobb R.R., Alderman E.M., Bethune J.L., RA Riordan J.F., Vallee B.L.; RT "Isolation and characterization of angiogenin, an angiogenic protein from RT human carcinoma cells."; RL Biochemistry 24:5480-5486(1985). RN [10] RP SUBCELLULAR LOCATION. RX PubMed=3663649; DOI=10.1021/bi00390a037; RA Shapiro R., Strydom D.J., Olson K.A., Vallee B.L.; RT "Isolation of angiogenin from normal human plasma."; RL Biochemistry 26:5141-5146(1987). RN [11] RP FUNCTION. RX PubMed=2424496; DOI=10.1021/bi00360a008; RA Shapiro R., Riordan J.F., Vallee B.L.; RT "Characteristic ribonucleolytic activity of human angiogenin."; RL Biochemistry 25:3527-3532(1986). RN [12] RP FUNCTION. RX PubMed=3122207; DOI=10.1073/pnas.84.24.8783; RA Shapiro R., Weremowicz S., Riordan J.F., Vallee B.L.; RT "Ribonucleolytic activity of angiogenin: essential histidine, lysine, and RT arginine residues."; RL Proc. Natl. Acad. Sci. U.S.A. 84:8783-8787(1987). RN [13] RP TISSUE SPECIFICITY. RX PubMed=2440105; DOI=10.1126/science.2440105; RA Weiner H.L., Weiner L.H., Swain J.L.; RT "Tissue distribution and developmental expression of the messenger RNA RT encoding angiogenin."; RL Science 237:280-282(1987). RN [14] RP FUNCTION. RX PubMed=3289612; DOI=10.1021/bi00407a007; RA Rybak S.M., Vallee B.L.; RT "Base cleavage specificity of angiogenin with Saccharomyces cerevisiae and RT Escherichia coli 5S RNAs."; RL Biochemistry 27:2288-2294(1988). RN [15] RP ACTIVITY REGULATION. RX PubMed=3243277; DOI=10.1002/j.1460-2075.1988.tb03310.x; RA Schneider R., Schneider-Scherzer E., Thurnher M., Auer B., Schweiger M.; RT "The primary structure of human ribonuclease/angiogenin inhibitor (RAI) RT discloses a novel highly diversified protein superfamily with a common RT repetitive module."; RL EMBO J. 7:4151-4156(1988). RN [16] RP FUNCTION, AND MUTAGENESIS OF ASP-140. RX PubMed=2459697; DOI=10.1073/pnas.85.19.7139; RA Harper J.W., Vallee B.L.; RT "Mutagenesis of aspartic acid-116 enhances the ribonucleolytic activity and RT angiogenic potency of angiogenin."; RL Proc. Natl. Acad. Sci. U.S.A. 85:7139-7143(1988). RN [17] RP FUNCTION. RX PubMed=2730651; DOI=10.1016/0006-291x(89)91569-6; RA Lee F.S., Vallee B.L.; RT "Characterization of ribonucleolytic activity of angiogenin towards tRNA."; RL Biochem. Biophys. Res. Commun. 161:121-126(1989). RN [18] RP FUNCTION. RX PubMed=1400510; DOI=10.1016/s0021-9258(19)36710-9; RA Saxena S.K., Rybak S.M., Davey R.T. Jr., Youle R.J., Ackerman E.J.; RT "Angiogenin is a cytotoxic, tRNA-specific ribonuclease in the RNase A RT superfamily."; RL J. Biol. Chem. 267:21982-21986(1992). RN [19] RP FUNCTION. RX PubMed=8448182; DOI=10.1016/0167-4838(93)90145-h; RA Bond M.D., Strydom D.J., Vallee B.L.; RT "Characterization and sequencing of rabbit, pig and mouse angiogenins: RT discernment of functionally important residues and regions."; RL Biochim. Biophys. Acta 1162:177-186(1993). RN [20] RP SUBCELLULAR LOCATION, AND NUCLEOLAR LOCALIZATION SIGNAL. RX PubMed=7945327; DOI=10.1006/bbrc.1994.2391; RA Moroianu J., Riordan J.F.; RT "Identification of the nucleolar targeting signal of human angiogenin."; RL Biochem. Biophys. Res. Commun. 203:1765-1772(1994). RN [21] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=8127865; DOI=10.1073/pnas.91.5.1677; RA Moroianu J., Riordan J.F.; RT "Nuclear translocation of angiogenin in proliferating endothelial cells is RT essential to its angiogenic activity."; RL Proc. Natl. Acad. Sci. U.S.A. 91:1677-1681(1994). RN [22] RP FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF 140-ASP-GLN-141 AND RP GLN-141. RX PubMed=8159680; DOI=10.1073/pnas.91.8.2920; RA Russo N., Shapiro R., Acharya K.R., Riordan J.F., Vallee B.L.; RT "Role of glutamine-117 in the ribonucleolytic activity of human RT angiogenin."; RL Proc. Natl. Acad. Sci. U.S.A. 91:2920-2924(1994). RN [23] RP FUNCTION, AND MUTAGENESIS OF ARG-29. RX PubMed=8570639; DOI=10.1073/pnas.93.2.804; RA Russo N., Acharya K.R., Vallee B.L., Shapiro R.; RT "A combined kinetic and modeling study of the catalytic center subsites of RT human angiogenin."; RL Proc. Natl. Acad. Sci. U.S.A. 93:804-808(1996). RN [24] RP FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF 143-ILE-PHE-144. RX PubMed=8622921; DOI=10.1073/pnas.93.8.3243; RA Russo N., Nobile V., Di Donato A., Riordan J.F., Vallee B.L.; RT "The C-terminal region of human angiogenin has a dual role in enzymatic RT activity."; RL Proc. Natl. Acad. Sci. U.S.A. 93:3243-3247(1996). RN [25] RP MUTAGENESIS OF HIS-32; GLN-36; LYS-64; ASN-92 AND GLU-132. RX PubMed=9050852; DOI=10.1073/pnas.94.5.1761; RA Chen C.Z., Shapiro R.; RT "Site-specific mutagenesis reveals differences in the structural bases for RT tight binding of RNase inhibitor to angiogenin and RNase A."; RL Proc. Natl. Acad. Sci. U.S.A. 94:1761-1766(1997). RN [26] RP FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF THR-68 AND THR-104. RX PubMed=9578571; DOI=10.1021/bi9800146; RA Shapiro R.; RT "Structural features that determine the enzymatic potency and specificity RT of human angiogenin: threonine-80 and residues 58-70 and 116-123."; RL Biochemistry 37:6847-6856(1998). RN [27] RP INTERACTION WITH RNH1, AND MUTAGENESIS OF ARG-29 AND LYS-64. RX PubMed=10413501; DOI=10.1021/bi990762a; RA Chen C.Z., Shapiro R.; RT "Superadditive and subadditive effects of 'hot spot' mutations within the RT interfaces of placental ribonuclease inhibitor with angiogenin and RT ribonuclease A."; RL Biochemistry 38:9273-9285(1999). RN [28] RP FUNCTION, SUBCELLULAR LOCATION, AND DNA-BINDING. RX PubMed=12051708; DOI=10.1016/s0006-291x(02)00479-5; RA Xu Z.P., Tsuji T., Riordan J.F., Hu G.F.; RT "The nuclear function of angiogenin in endothelial cells is related to rRNA RT production."; RL Biochem. Biophys. Res. Commun. 294:287-292(2002). RN [29] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=15735021; DOI=10.1158/0008-5472.can-04-2058; RA Tsuji T., Sun Y., Kishimoto K., Olson K.A., Liu S., Hirukawa S., Hu G.F.; RT "Angiogenin is translocated to the nucleus of HeLa cells and is involved in RT ribosomal RNA transcription and cell proliferation."; RL Cancer Res. 65:1352-1360(2005). RN [30] RP FUNCTION, ACTIVITY REGULATION, INTERACTION WITH RNH1, AND MUTAGENESIS OF RP 109-GLY-GLY-110. RX PubMed=19354288; DOI=10.1021/bi9005094; RA Dickson K.A., Kang D.K., Kwon Y.S., Kim J.C., Leland P.A., Kim B.M., RA Chang S.I., Raines R.T.; RT "Ribonuclease inhibitor regulates neovascularization by human angiogenin."; RL Biochemistry 48:3804-3806(2009). RN [31] RP FUNCTION, INTERACTION WITH RNH1, AND ACTIVITY REGULATION. RX PubMed=19332886; DOI=10.1083/jcb.200811106; RA Yamasaki S., Ivanov P., Hu G.F., Anderson P.; RT "Angiogenin cleaves tRNA and promotes stress-induced translational RT repression."; RL J. Cell Biol. 185:35-42(2009). RN [32] RP FUNCTION. RX PubMed=20129916; DOI=10.1074/jbc.m109.077560; RA Emara M.M., Ivanov P., Hickman T., Dawra N., Tisdale S., Kedersha N., RA Hu G.F., Anderson P.; RT "Angiogenin-induced tRNA-derived stress-induced RNAs promote stress-induced RT stress granule assembly."; RL J. Biol. Chem. 285:10959-10968(2010). RN [33] RP FUNCTION. RX PubMed=21855800; DOI=10.1016/j.molcel.2011.06.022; RA Ivanov P., Emara M.M., Villen J., Gygi S.P., Anderson P.; RT "Angiogenin-induced tRNA fragments inhibit translation initiation."; RL Mol. Cell 43:613-623(2011). RN [34] RP FUNCTION, ACTIVITY REGULATION, SUBCELLULAR LOCATION, AND INTERACTION WITH RP RNH1. RX PubMed=23843625; DOI=10.1242/jcs.134551; RA Pizzo E., Sarcinelli C., Sheng J., Fusco S., Formiggini F., Netti P., RA Yu W., D'Alessio G., Hu G.F.; RT "Ribonuclease/angiogenin inhibitor 1 regulates stress-induced subcellular RT localization of angiogenin to control growth and survival."; RL J. Cell Sci. 126:4308-4319(2013). RN [35] RP FUNCTION, INTERACTION WITH RNH1, AND SUBCELLULAR LOCATION. RX PubMed=27518564; DOI=10.1016/j.cell.2016.06.042; RA Goncalves K.A., Silberstein L., Li S., Severe N., Hu M.G., Yang H., RA Scadden D.T., Hu G.F.; RT "Angiogenin promotes hematopoietic regeneration by dichotomously regulating RT quiescence of stem and progenitor cells."; RL Cell 166:894-906(2016). RN [36] RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF HIS-37; ARG-90 AND RP ASN-92. RX PubMed=29100074; DOI=10.1016/j.cell.2017.10.005; RA Yu W., Goncalves K.A., Li S., Kishikawa H., Sun G., Yang H., Vanli N., RA Wu Y., Jiang Y., Hu M.G., Friedel R.H., Hu G.F.; RT "Plexin-B2 mediates physiologic and pathologic functions of angiogenin."; RL Cell 171:849-864(2017). RN [37] RP FUNCTION, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANT ALS9 RP LEU-136. RX PubMed=29748193; DOI=10.1261/rna.065516.117; RA Thomas S.P., Hoang T.T., Ressler V.T., Raines R.T.; RT "Human angiogenin is a potent cytotoxin in the absence of ribonuclease RT inhibitor."; RL RNA 24:1018-1027(2018). RN [38] RP FUNCTION. RX PubMed=31582561; DOI=10.1074/jbc.ra119.009272; RA Su Z., Kuscu C., Malik A., Shibata E., Dutta A.; RT "Angiogenin generates specific stress-induced tRNA halves and is not RT involved in tRF-3-mediated gene silencing."; RL J. Biol. Chem. 294:16930-16941(2019). RN [39] RP FUNCTION, ACTIVITY REGULATION, AND INTERACTION WITH RNH1. RX PubMed=32510170; DOI=10.15252/embj.2019103325; RA Bai R., Sun D., Chen M., Shi X., Luo L., Yao Z., Liu Y., Ge X., Gao X., RA Hu G.F., Zhou W., Sheng J., Xu Z.; RT "Myeloid cells protect intestinal epithelial barrier integrity through the RT angiogenin/plexin-B2 axis."; RL EMBO J. 39:e103325-e103325(2020). RN [40] RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 25-147, AND DISULFIDE BONDS. RX PubMed=8159679; DOI=10.1073/pnas.91.8.2915; RA Acharya K.R., Shapiro R., Allen S.C., Riordan J.F., Vallee B.L.; RT "Crystal structure of human angiogenin reveals the structural basis for its RT functional divergence from ribonuclease."; RL Proc. Natl. Acad. Sci. U.S.A. 91:2915-2919(1994). RN [41] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 25-147 IN COMPLEX WITH RNH1, RP DISULFIDE BONDS, AND SUBUNIT. RX PubMed=9311977; DOI=10.1093/emboj/16.17.5162; RA Papageorgiou A.C., Shapiro R., Acharya K.R.; RT "Molecular recognition of human angiogenin by placental ribonuclease RT inhibitor -- an X-ray crystallographic study at 2.0-A resolution."; RL EMBO J. 16:5162-5177(1997). RN [42] RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 26-147, ACTIVE SITES, AND RP DISULFIDE BONDS. RX PubMed=9918722; DOI=10.1006/jmbi.1998.2378; RA Leonidas D.D., Shapiro R., Allen S.C., Subbarao G.V., Veluraja K., RA Acharya K.R.; RT "Refined crystal structures of native human angiogenin and two active site RT variants: implications for the unique functional properties of an enzyme RT involved in neovascularisation during tumour growth."; RL J. Mol. Biol. 285:1209-1233(1999). RN [43] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 26-147 OF MUTANT GLY-141 IN RP COMPLEX WITH PHOSPHATE AND PYROPHOSPHATE, ACTIVE SITES, AND DISULFIDE RP BONDS. RX PubMed=11468363; DOI=10.1110/ps.13601; RA Leonidas D.D., Chavali G.B., Jardine A.M., Li S., Shapiro R., Acharya K.R.; RT "Binding of phosphate and pyrophosphate ions at the active site of human RT angiogenin as revealed by X-ray crystallography."; RL Protein Sci. 10:1669-1676(2001). RN [44] RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 26-147, DISULFIDE BONDS, AND RP MUTAGENESIS OF ASP-140; GLN-141 AND 143-ILE-PHE-144. RX PubMed=11851402; DOI=10.1021/bi015768q; RA Leonidas D.D., Shapiro R., Subbarao G.V., Russo A., Acharya K.R.; RT "Crystallographic studies on the role of the C-terminal segment of human RT angiogenin in defining enzymatic potency."; RL Biochemistry 41:2552-2562(2002). RN [45] RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 26-147, AND DISULFIDE BONDS. RX PubMed=12842050; DOI=10.1016/s0969-2126(03)00131-x; RA Chavali G.B., Papageorgiou A.C., Olson K.A., Fett J.W., Hu G., Shapiro R., RA Acharya K.R.; RT "The crystal structure of human angiogenin in complex with an antitumor RT neutralizing antibody."; RL Structure 11:875-885(2003). RN [46] RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF MUTANTS ASP-68 AND ALA-104, AND RP DISULFIDE BONDS. RX PubMed=14756559; DOI=10.1021/bi035654+; RA Holloway D.E., Chavali G.B., Hares M.C., Baker M.D., Subbarao G.V., RA Shapiro R., Acharya K.R.; RT "Crystallographic studies on structural features that determine the RT enzymatic specificity and potency of human angiogenin: Thr44, Thr80, and RT residues 38-41."; RL Biochemistry 43:1230-1241(2004). RN [47] RP STRUCTURE BY NMR, AND DISULFIDE BONDS. RX PubMed=9461294; DOI=10.1111/j.1432-1033.1997.00712.x; RA Lequin O., Thuering H., Robin M., Lallemand J.-Y.; RT "Three-dimensional solution structure of human angiogenin determined by RT 1H,15N-NMR spectroscopy -- characterization of histidine protonation states RT and pKa values."; RL Eur. J. Biochem. 250:712-726(1997). RN [48] {ECO:0007744|PDB:4AHD, ECO:0007744|PDB:4AHE, ECO:0007744|PDB:4AHF, ECO:0007744|PDB:4AHG, ECO:0007744|PDB:4AHH, ECO:0007744|PDB:4AHI, ECO:0007744|PDB:4AHJ, ECO:0007744|PDB:4AHK, ECO:0007744|PDB:4AHL, ECO:0007744|PDB:4AHM, ECO:0007744|PDB:4AHN} RP X-RAY CRYSTALLOGRAPHY (1.04 ANGSTROMS) OF 24-147, FUNCTION, AND SUBCELLULAR RP LOCATION. RX PubMed=23047679; DOI=10.1038/ncomms2126; RA Thiyagarajan N., Ferguson R., Subramanian V., Acharya K.R.; RT "Structural and molecular insights into the mechanism of action of human RT angiogenin-ALS variants in neurons."; RL Nat. Commun. 3:1121-1121(2012). RN [49] RP 3D-STRUCTURE MODELING. RX PubMed=22384259; DOI=10.1371/journal.pone.0032479; RA Padhi A.K., Kumar H., Vasaikar S.V., Jayaram B., Gomes J.; RT "Mechanisms of loss of functions of human angiogenin variants implicated in RT amyotrophic lateral sclerosis."; RL PLoS ONE 7:E32479-E32479(2012). RN [50] {ECO:0007744|PDB:5M9A, ECO:0007744|PDB:5M9C, ECO:0007744|PDB:5M9G, ECO:0007744|PDB:5M9J, ECO:0007744|PDB:5M9M, ECO:0007744|PDB:5M9P, ECO:0007744|PDB:5M9Q, ECO:0007744|PDB:5M9R, ECO:0007744|PDB:5M9S, ECO:0007744|PDB:5M9T, ECO:0007744|PDB:5M9V} RP X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS) OF 25-147, FUNCTION, AND DISULFIDE RP BONDS. RX PubMed=28176817; DOI=10.1038/srep41996; RA Bradshaw W.J., Rehman S., Pham T.T., Thiyagarajan N., Lee R.L., RA Subramanian V., Acharya K.R.; RT "Structural insights into human angiogenin variants implicated in RT Parkinson's disease and Amyotrophic Lateral Sclerosis."; RL Sci. Rep. 7:41996-41996(2017). RN [51] RP STRUCTURE BY NMR. RX PubMed=33535464; DOI=10.3390/ijms22031439; RA Fagagnini A., Garavis M., Gomez-Pinto I., Fasoli S., Gotte G., RA Laurents D.V.; RT "NMR Characterization of Angiogenin Variants and tRNAAla Products Impacting RT Aberrant Protein Oligomerization."; RL Int. J. Mol. Sci. 22:0-0(2021). RN [52] {ECO:0007744|PDB:7PNJ, ECO:0007744|PDB:7PNP, ECO:0007744|PDB:7PNR} RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 25-145, INTERACTION WITH PCNA, RP AND DISULFIDE BONDS. RX PubMed=37218877; DOI=10.1021/acs.biochem.3c00158; RA Papaioannou O.S.E., Tsika A.C., Rovoli M., Papadopoulos G.E., RA Kontopidis G., Spyroulias G.A., Leonidas D.D.; RT "Structural and biochemical characterization of the human angiogenin- RT proliferating cell nuclear antigen interaction."; RL Biochemistry 62:1706-1715(2023). RN [53] RP STRUCTURE BY ELECTRON MICROSCOPY (3.0 ANGSTROMS) IN COMPLEX WITH TRNA AND RP RIBOSOME, ACTIVE SITES, DISULFIDE BONDS, FUNCTION, ACTIVITY REGULATION, RP CHARACTERIZATION OF VARIANT ALS9 GLU-78, AND MUTAGENESIS OF HIS-37. RX PubMed=38718836; DOI=10.1038/s41586-024-07508-8; RA Loveland A.B., Koh C.S., Ganesan R., Jacobson A., Korostelev A.A.; RT "Structural mechanism of angiogenin activation by the ribosome."; RL Nature 630:769-776(2024). RN [54] RP VARIANT ALS9 ILE-64. RX PubMed=15557516; DOI=10.1212/01.wnl.0000144344.39103.f6; RA Greenway M.J., Alexander M.D., Ennis S., Traynor B.J., Corr B., Frost E., RA Green A., Hardiman O.; RT "A novel candidate region for ALS on chromosome 14q11.2."; RL Neurology 63:1936-1938(2004). RN [55] RP VARIANTS ALS9 LEU-36; ILE-41; GLU-41; LYS-55; TRP-63; ILE-64 AND VAL-70. RX PubMed=16501576; DOI=10.1038/ng1742; RA Greenway M.J., Andersen P.M., Russ C., Ennis S., Cashman S., Donaghy C., RA Patterson V., Swingler R., Kieran D., Prehn J., Morrison K.E., Green A., RA Acharya K.R., Brown R.H. Jr., Hardiman O.; RT "ANG mutations segregate with familial and 'sporadic' amyotrophic lateral RT sclerosis."; RL Nat. Genet. 38:411-413(2006). RN [56] RP VARIANTS ALS9 SER-20; ILE-41; ASN-52 AND LEU-136, CHARACTERIZATION OF RP VARIANTS ALS9 ILE-41; ASN-52 AND LEU-136, AND TISSUE SPECIFICITY. RX PubMed=17886298; DOI=10.1002/ana.21221; RA Wu D., Yu W., Kishikawa H., Folkerth R.D., Iafrate A.J., Shen Y., Xin W., RA Sims K., Hu G.-F.; RT "Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis."; RL Ann. Neurol. 62:609-617(2007). RN [57] RP CHARACTERIZATION OF VARIANTS ALS9 LEU-36; ILE-41; GLU-41; LYS-55; TRP-63; RP ILE-64 AND VAL-70, AND CHARACTERIZATION OF VARIANT ALS9 VAL-70. RX PubMed=17900154; DOI=10.1021/bi701333h; RA Crabtree B., Thiyagarajan N., Prior S.H., Wilson P., Iyer S., Ferns T., RA Shapiro R., Brew K., Subramanian V., Acharya K.R.; RT "Characterization of human angiogenin variants implicated in amyotrophic RT lateral sclerosis."; RL Biochemistry 46:11810-11818(2007). RN [58] RP VARIANTS ALS9 VAL-70 AND HIS-145. RX PubMed=18852347; DOI=10.1001/archneur.65.10.1333; RG French Amyotrophic Lateral Sclerosis (ALS) Study Group; RA Paubel A., Violette J., Amy M., Praline J., Meininger V., Camu W., RA Corcia P., Andres C.R., Vourc'h P.; RT "Mutations of the ANG gene in French patients with sporadic amyotrophic RT lateral sclerosis."; RL Arch. Neurol. 65:1333-1336(2008). RN [59] RP VARIANTS ALS9 SER-12; SER-20; VAL-70; ILE-137 AND ARG-138. RX PubMed=18087731; DOI=10.1007/s10048-007-0111-3; RA Gellera C., Colombrita C., Ticozzi N., Castellotti B., Bragato C., RA Ratti A., Taroni F., Silani V.; RT "Identification of new ANG gene mutations in a large cohort of Italian RT patients with amyotrophic lateral sclerosis."; RL Neurogenetics 9:33-40(2008). RN [60] RP VARIANT ALS9 GLU-41. RX PubMed=19153377; DOI=10.1212/01.wnl.0000339487.84908.00; RA van Es M.A., Diekstra F.P., Veldink J.H., Baas F., Bourque P.R., RA Schelhaas H.J., Strengman E., Hennekam E.A., Lindhout D., Ophoff R.A., RA van den Berg L.H.; RT "A case of ALS-FTD in a large FALS pedigree with a K17I ANG mutation."; RL Neurology 72:287-288(2009). RN [61] RP INVOLVEMENT IN ALS9. RX PubMed=17703939; DOI=10.1016/j.nmd.2007.07.003; RA Conforti F.L., Sprovieri T., Mazzei R., Ungaro C., La Bella V., RA Tessitore A., Patitucci A., Magariello A., Gabriele A.L., Tedeschi G., RA Simone I.L., Majorana G., Valentino P., Condino F., Bono F., Monsurro M.R., RA Muglia M., Quattrone A.; RT "A novel angiogenin gene mutation in a sporadic patient with amyotrophic RT lateral sclerosis from southern Italy."; RL Neuromuscul. Disord. 18:68-70(2008). RN [62] RP VARIANTS ALS9 LEU-12 AND GLU-78. RX PubMed=19363631; DOI=10.1007/s00415-009-5124-4; RA Fernandez-Santiago R., Hoenig S., Lichtner P., Sperfeld A.D., Sharma M., RA Berg D., Weichenrieder O., Illig T., Eger K., Meyer T., Anneser J., RA Muench C., Zierz S., Gasser T., Ludolph A.; RT "Identification of novel Angiogenin (ANG) gene missense variants in German RT patients with amyotrophic lateral sclerosis."; RL J. Neurol. 256:1337-1342(2009). RN [63] RP VARIANTS ALS9 LEU-12; SER-12; ASP-15; GLN-20; SER-20; LEU-36; GLU-41; RP ASN-52; LYS-55; TRP-63; ILE-64; GLU-64; SER-104; ILE-124; LEU-136; ILE-137; RP ARG-138 AND HIS-145, AND VARIANTS ALA-13; ASP-17; ARG-37; VAL-46; ARG-78; RP GLN-119 AND CYS-145. RX PubMed=22190368; DOI=10.1002/ana.22611; RA van Es M.A., Schelhaas H.J., van Vught P.W., Ticozzi N., Andersen P.M., RA Groen E.J., Schulte C., Blauw H.M., Koppers M., Diekstra F.P., Fumoto K., RA LeClerc A.L., Keagle P., Bloem B.R., Scheffer H., van Nuenen B.F., RA van Blitterswijk M., van Rheenen W., Wills A.M., Lowe P.P., Hu G.F., Yu W., RA Kishikawa H., Wu D., Folkerth R.D., Mariani C., Goldwurm S., Pezzoli G., RA Van Damme P., Lemmens R., Dahlberg C., Birve A., Fernandez-Santiago R., RA Waibel S., Klein C., Weber M., van der Kooi A.J., de Visser M., Verbaan D., RA van Hilten J.J., Heutink P., Hennekam E.A., Cuppen E., Berg D., RA Brown R.H. Jr., Silani V., Gasser T., Ludolph A.C., Robberecht W., RA Ophoff R.A., Veldink J.H., Pasterkamp R.J., de Bakker P.I., Landers J.E., RA van de Warrenburg B.P., van den Berg L.H.; RT "Angiogenin variants in Parkinson disease and amyotrophic lateral RT sclerosis."; RL Ann. Neurol. 70:964-973(2011). RN [64] RP VARIANTS ALS9 HIS-38; ILE-41 AND GLY-46. RX PubMed=22292843; DOI=10.3109/17482968.2011.643899; RA Brown J.A., Min J., Staropoli J.F., Collin E., Bi S., Feng X., Barone R., RA Cao Y., O'Malley L., Xin W., Mullen T.E., Sims K.B.; RT "SOD1, ANG, TARDBP and FUS mutations in amyotrophic lateral sclerosis: a RT United States clinical testing lab experience."; RL Amyotroph. Lateral Scler. 13:217-222(2012). RN [65] RP VARIANT ALS9 ILE-127. RX PubMed=22292798; DOI=10.3109/17482968.2011.643900; RA Zou Z.Y., Wang X.N., Liu M.S., Sun Q., Li X.G., Cui L.Y., Kong J.; RT "Identification of a novel missense mutation in angiogenin in a Chinese RT amyotrophic lateral sclerosis cohort."; RL Amyotroph. Lateral Scler. 13:270-275(2012). RN [66] RP VARIANT ALS9 GLY-46, CHARACTERIZATION OF VARIANT ALS9 GLY-46, MUTAGENESIS RP OF LEU-59, SUBUNIT, AND SUBCELLULAR LOCATION. RX PubMed=25372031; DOI=10.1371/journal.pone.0111963; RA Padhi A.K., Banerjee K., Gomes J., Banerjee M.; RT "Computational and functional characterization of Angiogenin mutations, and RT correlation with amyotrophic lateral sclerosis."; RL PLoS ONE 9:E111963-E111963(2014). CC -!- FUNCTION: Secreted ribonuclease that can either promote or restrict CC cell proliferation of target cells, depending on the context CC (PubMed:12051708, PubMed:1400510, PubMed:19332886, PubMed:20129916, CC PubMed:21855800, PubMed:23047679, PubMed:23843625, PubMed:2424496, CC PubMed:2459697, PubMed:2730651, PubMed:27518564, PubMed:28176817, CC PubMed:29100074, PubMed:29748193, PubMed:3122207, PubMed:32510170, CC PubMed:38718836, PubMed:8159680, PubMed:8570639, PubMed:8622921, CC PubMed:9578571). Endocytosed in target cells via its receptor PLXNB2 CC and translocates to the cytoplasm or nucleus (PubMed:29100074, CC PubMed:32510170). Under stress conditions, localizes to the cytoplasm CC and promotes the assembly of stress granules (SGs): specifically CC cleaves a subset of tRNAs within anticodon loops to produce tRNA- CC derived stress-induced fragments (tiRNAs), resulting in translation CC repression and inhibition of cell proliferation (PubMed:1400510, CC PubMed:19332886, PubMed:20129916, PubMed:21855800, PubMed:23047679, CC PubMed:27518564, PubMed:29100074, PubMed:29748193, PubMed:32510170, CC PubMed:38718836). tiRNas also prevent formation of apoptosome, thereby CC promoting cell survival (By similarity). Preferentially cleaves RNAs CC between a pyrimidine and an adenosine residue, suggesting that it CC cleaves the anticodon loop of tRNA(Ala) (32-UUAGCAU-38) after positions CC 33 and 36 (PubMed:3289612, PubMed:38718836). Cleaves a subset of tRNAs, CC including tRNA(Ala), tRNA(Glu), tRNA(Gly), tRNA(Lys), tRNA(Val), CC tRNA(His), tRNA(Asp) and tRNA(Sec) (PubMed:31582561). Under growth CC conditions and in differentiated cells, translocates to the nucleus and CC stimulates ribosomal RNA (rRNA) transcription, including that CC containing the initiation site sequences of 45S rRNA, thereby promoting CC cell growth and proliferation (PubMed:12051708, PubMed:15735021, CC PubMed:27518564, PubMed:29100074, PubMed:8127865). Angiogenin induces CC vascularization of normal and malignant tissues via its ability to CC promote rRNA transcription (PubMed:19354288, PubMed:4074709, CC PubMed:8448182). Involved in hematopoietic stem and progenitor cell CC (HSPC) growth and survival by promoting rRNA transcription in growth CC conditions and inhibiting translation in response to stress, CC respectively (PubMed:27518564). Mediates the crosstalk between myeloid CC and intestinal epithelial cells to protect the intestinal epithelial CC barrier integrity: secreted by myeloid cells and promotes intestinal CC epithelial cells proliferation and survival (PubMed:32510170). Also CC mediates osteoclast-endothelial cell crosstalk in growing bone: CC produced by osteoclasts and protects the neighboring vascular cells CC against senescence by promoting rRNA transcription (By similarity). CC {ECO:0000250|UniProtKB:P21570, ECO:0000269|PubMed:12051708, CC ECO:0000269|PubMed:1400510, ECO:0000269|PubMed:15735021, CC ECO:0000269|PubMed:19332886, ECO:0000269|PubMed:19354288, CC ECO:0000269|PubMed:20129916, ECO:0000269|PubMed:21855800, CC ECO:0000269|PubMed:23047679, ECO:0000269|PubMed:23843625, CC ECO:0000269|PubMed:2424496, ECO:0000269|PubMed:2459697, CC ECO:0000269|PubMed:2730651, ECO:0000269|PubMed:27518564, CC ECO:0000269|PubMed:28176817, ECO:0000269|PubMed:29100074, CC ECO:0000269|PubMed:29748193, ECO:0000269|PubMed:3122207, CC ECO:0000269|PubMed:31582561, ECO:0000269|PubMed:32510170, CC ECO:0000269|PubMed:3289612, ECO:0000269|PubMed:38718836, CC ECO:0000269|PubMed:4074709, ECO:0000269|PubMed:8127865, CC ECO:0000269|PubMed:8159680, ECO:0000269|PubMed:8448182, CC ECO:0000269|PubMed:8570639, ECO:0000269|PubMed:8622921, CC ECO:0000269|PubMed:9578571}. CC -!- ACTIVITY REGULATION: Has weak tRNA ribonuclease activity by itself due CC to partial autoinhibition by its C-terminus (residues 140-147), which CC folds into a short alpha-helix that partially occludes the substrate- CC binding site (PubMed:38718836, PubMed:8159680, PubMed:8622921, CC PubMed:9578571). In absence of stress, the ribonuclease activity is CC inhibited by RNH1 in the cytoplasm (PubMed:19332886, PubMed:19354288, CC PubMed:23843625, PubMed:3243277, PubMed:32510170, PubMed:38718836). In CC response to stress, dissociates from RNH1 in the cytoplasm and CC associates with cytoplasmic ribosomes with vacant A-sites: ribosomes CC directly activate the tRNA ribonuclease activity of ANG by refolding CC the C-terminal alpha-helix (PubMed:38718836). In response to stress, CC the angiogenic activity of ANG is inhibited by RNH1 in the nucleus CC (PubMed:23843625). {ECO:0000269|PubMed:19332886, CC ECO:0000269|PubMed:19354288, ECO:0000269|PubMed:23843625, CC ECO:0000269|PubMed:3243277, ECO:0000269|PubMed:32510170, CC ECO:0000269|PubMed:38718836, ECO:0000269|PubMed:8159680, CC ECO:0000269|PubMed:8622921, ECO:0000269|PubMed:9578571}. CC -!- SUBUNIT: Homodimer (PubMed:25372031). Interacts with RNH1; inhibiting CC ANG ribonuclease activity (PubMed:10413501, PubMed:19332886, CC PubMed:19354288, PubMed:23843625, PubMed:27518564, PubMed:3243277, CC PubMed:32510170, PubMed:9311977). Interacts with PCNA CC (PubMed:37218877). {ECO:0000269|PubMed:10413501, CC ECO:0000269|PubMed:19332886, ECO:0000269|PubMed:19354288, CC ECO:0000269|PubMed:23843625, ECO:0000269|PubMed:25372031, CC ECO:0000269|PubMed:27518564, ECO:0000269|PubMed:3243277, CC ECO:0000269|PubMed:32510170, ECO:0000269|PubMed:37218877, CC ECO:0000269|PubMed:9311977}. CC -!- INTERACTION: CC P03950; P35609: ACTN2; NbExp=4; IntAct=EBI-525291, EBI-77797; CC P03950; P19883: FST; NbExp=3; IntAct=EBI-525291, EBI-1571188; CC P03950; P12004: PCNA; NbExp=4; IntAct=EBI-525291, EBI-358311; CC P03950; Q03405: PLAUR; NbExp=5; IntAct=EBI-525291, EBI-716505; CC P03950; P13489: RNH1; NbExp=6; IntAct=EBI-525291, EBI-1237106; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:23047679, CC ECO:0000269|PubMed:29748193, ECO:0000269|PubMed:3663649}. Nucleus CC {ECO:0000269|PubMed:12051708, ECO:0000269|PubMed:15735021, CC ECO:0000269|PubMed:23047679, ECO:0000269|PubMed:23843625, CC ECO:0000269|PubMed:25372031, ECO:0000269|PubMed:29100074, CC ECO:0000269|PubMed:8127865}. Nucleus, nucleolus CC {ECO:0000269|PubMed:12051708, ECO:0000269|PubMed:7945327}. Cytoplasm, CC Stress granule {ECO:0000269|PubMed:23843625, CC ECO:0000269|PubMed:27518564, ECO:0000269|PubMed:29100074}. Note=The CC secreted protein is rapidly endocytosed by target cells following CC interaction with PLXNB2 receptor and translocated to the cytoplasm and CC nucleus (PubMed:29100074). In the nucleus, accumulates in the nucleolus CC and binds to DNA (PubMed:12051708). {ECO:0000269|PubMed:12051708, CC ECO:0000269|PubMed:29100074}. CC -!- TISSUE SPECIFICITY: Expressed predominantly in the liver CC (PubMed:2440105). Also detected in endothelial cells and spinal cord CC neurons (PubMed:17886298, PubMed:2440105). CC {ECO:0000269|PubMed:17886298, ECO:0000269|PubMed:2440105}. CC -!- DEVELOPMENTAL STAGE: Low level expression in the developing fetus, CC increased in the neonate, and maximal in the adult. CC {ECO:0000269|PubMed:2440105}. CC -!- DISEASE: Amyotrophic lateral sclerosis 9 (ALS9) [MIM:611895]: A CC neurodegenerative disorder affecting upper motor neurons in the brain CC and lower motor neurons in the brain stem and spinal cord, resulting in CC fatal paralysis. Sensory abnormalities are absent. The pathologic CC hallmarks of the disease include pallor of the corticospinal tract due CC to loss of motor neurons, presence of ubiquitin-positive inclusions CC within surviving motor neurons, and deposition of pathologic CC aggregates. The etiology of amyotrophic lateral sclerosis is likely to CC be multifactorial, involving both genetic and environmental factors. CC The disease is inherited in 5-10% of the cases. CC {ECO:0000269|PubMed:15557516, ECO:0000269|PubMed:16501576, CC ECO:0000269|PubMed:17703939, ECO:0000269|PubMed:17886298, CC ECO:0000269|PubMed:17900154, ECO:0000269|PubMed:18087731, CC ECO:0000269|PubMed:18852347, ECO:0000269|PubMed:19153377, CC ECO:0000269|PubMed:19332886, ECO:0000269|PubMed:19363631, CC ECO:0000269|PubMed:22190368, ECO:0000269|PubMed:22292798, CC ECO:0000269|PubMed:22292843, ECO:0000269|PubMed:25372031, CC ECO:0000269|PubMed:29748193, ECO:0000269|PubMed:38718836}. Note=Disease CC susceptibility is associated with variants affecting the gene CC represented in this entry. CC -!- SIMILARITY: Belongs to the pancreatic ribonuclease family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH20704.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Functional Glycomics Gateway - Glycan Binding; CC Note=Angiogenin; CC URL="http://www.functionalglycomics.org/glycomics/GBPServlet?&operationType=view&cbpId=cbp_hum_other_803"; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/635/ANG"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M11567; AAA51678.1; -; Genomic_DNA. DR EMBL; AF449647; AAL67710.1; -; Genomic_DNA. DR EMBL; AF449648; AAL67711.1; -; Genomic_DNA. DR EMBL; AF449649; AAL67712.1; -; Genomic_DNA. DR EMBL; AF449650; AAL67713.1; -; Genomic_DNA. DR EMBL; AF449651; AAL67714.1; -; Genomic_DNA. DR EMBL; FJ236304; ACI45236.1; -; mRNA. DR EMBL; CR407633; CAG28561.1; -; mRNA. DR EMBL; AK313989; BAG36701.1; -; mRNA. DR EMBL; CH471078; EAW66450.1; -; Genomic_DNA. DR EMBL; CH471078; EAW66451.1; -; Genomic_DNA. DR EMBL; BC020704; AAH20704.1; ALT_INIT; mRNA. DR EMBL; BC054880; AAH54880.1; -; mRNA. DR EMBL; BC062698; AAH62698.1; -; mRNA. DR CCDS; CCDS9554.1; -. DR PIR; A90498; NRHUAG. DR RefSeq; NP_001091046.1; NM_001097577.3. DR RefSeq; NP_001136.1; NM_001145.4. DR RefSeq; NP_001372200.1; NM_001385271.1. DR RefSeq; NP_001372201.1; NM_001385272.1. DR RefSeq; NP_001372202.1; NM_001385273.1. DR RefSeq; NP_001372203.1; NM_001385274.1. DR PDB; 1A4Y; X-ray; 2.00 A; B/E=25-147. DR PDB; 1ANG; X-ray; 2.40 A; A=25-147. DR PDB; 1AWZ; NMR; -; A=25-147. DR PDB; 1B1E; X-ray; 2.00 A; A=25-147. DR PDB; 1B1I; X-ray; 1.80 A; A=26-147. DR PDB; 1B1J; X-ray; 2.00 A; A=25-147. DR PDB; 1GV7; X-ray; 2.10 A; A=26-145. DR PDB; 1H0D; X-ray; 2.00 A; C=26-147. DR PDB; 1H52; X-ray; 2.00 A; A=25-147. DR PDB; 1H53; X-ray; 2.00 A; A=26-147. DR PDB; 1HBY; X-ray; 2.00 A; A=25-147. DR PDB; 1K58; X-ray; 2.70 A; A=25-147. DR PDB; 1K59; X-ray; 1.80 A; A=25-147. DR PDB; 1K5A; X-ray; 2.33 A; A=25-147. DR PDB; 1K5B; X-ray; 1.80 A; A=25-144. DR PDB; 1UN3; X-ray; 1.70 A; A=26-147. DR PDB; 1UN4; X-ray; 2.10 A; A=26-147. DR PDB; 1UN5; X-ray; 2.60 A; A=25-147. DR PDB; 2ANG; X-ray; 2.00 A; A=25-147. DR PDB; 4AHD; X-ray; 2.47 A; A/B=25-147. DR PDB; 4AHE; X-ray; 2.08 A; A=25-147. DR PDB; 4AHF; X-ray; 2.12 A; A=25-147. DR PDB; 4AHG; X-ray; 2.45 A; A=25-147. DR PDB; 4AHH; X-ray; 2.50 A; A=25-147. DR PDB; 4AHI; X-ray; 2.80 A; A=25-147. DR PDB; 4AHJ; X-ray; 2.03 A; A=25-147. DR PDB; 4AHK; X-ray; 1.97 A; A/B=25-147. DR PDB; 4AHL; X-ray; 2.05 A; A=25-147. DR PDB; 4AHM; X-ray; 1.96 A; A=25-147. DR PDB; 4AHN; X-ray; 2.98 A; A=25-147. DR PDB; 4AOH; X-ray; 1.04 A; A=24-147. DR PDB; 4B36; X-ray; 1.76 A; A/B=25-147. DR PDB; 5EOP; X-ray; 1.35 A; A=26-146. DR PDB; 5EPZ; X-ray; 1.85 A; A=26-145. DR PDB; 5EQO; X-ray; 2.40 A; A=25-145. DR PDB; 5M9A; X-ray; 1.95 A; A=25-147. DR PDB; 5M9C; X-ray; 2.05 A; A=25-147. DR PDB; 5M9G; X-ray; 2.28 A; A=25-147. DR PDB; 5M9J; X-ray; 1.90 A; A=25-147. DR PDB; 5M9M; X-ray; 1.65 A; A/B/C/D=25-147. DR PDB; 5M9P; X-ray; 1.80 A; A=25-147. DR PDB; 5M9Q; X-ray; 1.35 A; A=25-147. DR PDB; 5M9R; X-ray; 1.44 A; A/B=25-147. DR PDB; 5M9S; X-ray; 1.85 A; A=25-147. DR PDB; 5M9T; X-ray; 2.20 A; A/B=25-147. DR PDB; 5M9V; X-ray; 1.70 A; A=25-147. DR PDB; 7NPM; X-ray; 1.86 A; AAA=26-146. DR PDB; 7PNJ; X-ray; 3.10 A; A=25-145. DR PDB; 7PNP; X-ray; 1.80 A; A=25-147. DR PDB; 7PNR; X-ray; 1.60 A; A=25-145. DR PDB; 8AF0; X-ray; 2.43 A; A/B=25-147. DR PDB; 9BDL; EM; 2.80 A; ANG=1-147. DR PDB; 9BDN; EM; 3.10 A; ANG=1-147. DR PDB; 9BDP; EM; 3.70 A; ANG=1-147. DR PDBsum; 1A4Y; -. DR PDBsum; 1ANG; -. DR PDBsum; 1AWZ; -. DR PDBsum; 1B1E; -. DR PDBsum; 1B1I; -. DR PDBsum; 1B1J; -. DR PDBsum; 1GV7; -. DR PDBsum; 1H0D; -. DR PDBsum; 1H52; -. DR PDBsum; 1H53; -. DR PDBsum; 1HBY; -. DR PDBsum; 1K58; -. DR PDBsum; 1K59; -. DR PDBsum; 1K5A; -. DR PDBsum; 1K5B; -. DR PDBsum; 1UN3; -. DR PDBsum; 1UN4; -. DR PDBsum; 1UN5; -. DR PDBsum; 2ANG; -. DR PDBsum; 4AHD; -. DR PDBsum; 4AHE; -. DR PDBsum; 4AHF; -. DR PDBsum; 4AHG; -. DR PDBsum; 4AHH; -. DR PDBsum; 4AHI; -. DR PDBsum; 4AHJ; -. DR PDBsum; 4AHK; -. DR PDBsum; 4AHL; -. DR PDBsum; 4AHM; -. DR PDBsum; 4AHN; -. DR PDBsum; 4AOH; -. DR PDBsum; 4B36; -. DR PDBsum; 5EOP; -. DR PDBsum; 5EPZ; -. DR PDBsum; 5EQO; -. DR PDBsum; 5M9A; -. DR PDBsum; 5M9C; -. DR PDBsum; 5M9G; -. DR PDBsum; 5M9J; -. DR PDBsum; 5M9M; -. DR PDBsum; 5M9P; -. DR PDBsum; 5M9Q; -. DR PDBsum; 5M9R; -. DR PDBsum; 5M9S; -. DR PDBsum; 5M9T; -. DR PDBsum; 5M9V; -. DR PDBsum; 7NPM; -. DR PDBsum; 7PNJ; -. DR PDBsum; 7PNP; -. DR PDBsum; 7PNR; -. DR PDBsum; 8AF0; -. DR PDBsum; 9BDL; -. DR PDBsum; 9BDN; -. DR PDBsum; 9BDP; -. DR AlphaFoldDB; P03950; -. DR EMDB; EMD-44461; -. DR EMDB; EMD-44463; -. DR EMDB; EMD-44464; -. DR SMR; P03950; -. DR BioGRID; 106780; 9. DR CORUM; P03950; -. DR FunCoup; P03950; 165. DR IntAct; P03950; 125. DR MINT; P03950; -. DR STRING; 9606.ENSP00000336762; -. DR BindingDB; P03950; -. DR ChEMBL; CHEMBL5829; -. DR DrugBank; DB09130; Copper. DR GlyGen; P03950; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P03950; -. DR PhosphoSitePlus; P03950; -. DR BioMuta; ANG; -. DR DMDM; 113873; -. DR jPOST; P03950; -. DR MassIVE; P03950; -. DR PaxDb; 9606-ENSP00000336762; -. DR PeptideAtlas; P03950; -. DR ProteomicsDB; 51619; -. DR TopDownProteomics; P03950; -. DR ABCD; P03950; 1 sequenced antibody. DR Antibodypedia; 22061; 470 antibodies from 35 providers. DR DNASU; 283; -. DR Ensembl; ENST00000336811.10; ENSP00000336762.6; ENSG00000214274.11. DR Ensembl; ENST00000397990.5; ENSP00000381077.4; ENSG00000214274.11. DR GeneID; 283; -. DR KEGG; hsa:283; -. DR MANE-Select; ENST00000397990.5; ENSP00000381077.4; NM_001097577.3; NP_001091046.1. DR AGR; HGNC:483; -. DR ClinPGx; PA24790; -. DR CTD; 283; -. DR DisGeNET; 283; -. DR GeneCards; ANG; -. DR HGNC; HGNC:483; ANG. DR HPA; ENSG00000214274; Tissue enriched (liver). DR MalaCards; ANG; -. DR MIM; 105850; gene. DR MIM; 611895; phenotype. DR OpenTargets; ENSG00000214274; -. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR VEuPathDB; HostDB:ENSG00000214274; -. DR eggNOG; ENOG502S9Q1; Eukaryota. DR GeneTree; ENSGT00940000162981; -. DR HOGENOM; CLU_117006_3_1_1; -. DR InParanoid; P03950; -. DR OMA; FIHGNKG; -. DR OrthoDB; 8573660at2759; -. DR PAN-GO; P03950; 7 GO annotations based on evolutionary models. DR PhylomeDB; P03950; -. DR PathwayCommons; P03950; -. DR Reactome; R-HSA-418990; Adherens junctions interactions. DR Reactome; R-HSA-9708296; tRNA-derived small RNA (tsRNA or tRNA-related fragment, tRF) biogenesis. DR SABIO-RK; P03950; -. DR SignaLink; P03950; -. DR SIGNOR; P03950; -. DR Agora; ENSG00000214274; -. DR BioGRID-ORCS; 283; 19 hits in 1148 CRISPR screens. DR CD-CODE; DEE660B4; Stress granule. DR EvolutionaryTrace; P03950; -. DR GeneWiki; Angiogenin; -. DR GenomeRNAi; 283; -. DR Pharos; P03950; Tbio. DR PRO; PR:P03950; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; P03950; protein. DR Bgee; ENSG00000214274; Expressed in right lobe of liver and 158 other cell types or tissues. DR ExpressionAtlas; P03950; baseline and differential. DR GO; GO:0015629; C:actin cytoskeleton; IDA:HPA. DR GO; GO:0032311; C:angiogenin-PRI complex; IDA:MGI. DR GO; GO:0005604; C:basement membrane; IDA:UniProtKB. DR GO; GO:0005694; C:chromosome; IDA:HPA. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0010494; C:cytoplasmic stress granule; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0030139; C:endocytic vesicle; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0030426; C:growth cone; ISS:UniProtKB. DR GO; GO:0043025; C:neuronal cell body; ISS:UniProtKB. DR GO; GO:0005730; C:nucleolus; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0003779; F:actin binding; IDA:UniProtKB. DR GO; GO:0005507; F:copper ion binding; IDA:UniProtKB. DR GO; GO:0003677; F:DNA binding; IC:UniProtKB. DR GO; GO:0004519; F:endonuclease activity; TAS:UniProtKB. DR GO; GO:0008201; F:heparin binding; IDA:UniProtKB. DR GO; GO:0016787; F:hydrolase activity; IEA:UniProtKB-KW. DR GO; GO:0042277; F:peptide binding; IDA:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB. DR GO; GO:0048018; F:receptor ligand activity; IDA:UniProt. DR GO; GO:0043022; F:ribosome binding; IDA:UniProtKB. DR GO; GO:0004521; F:RNA endonuclease activity; TAS:Reactome. DR GO; GO:0004540; F:RNA nuclease activity; IDA:UniProtKB. DR GO; GO:0019843; F:rRNA binding; TAS:UniProtKB. DR GO; GO:0005102; F:signaling receptor binding; IDA:UniProtKB. DR GO; GO:0004549; F:tRNA-specific ribonuclease activity; IDA:UniProtKB. DR GO; GO:0030041; P:actin filament polymerization; ISS:UniProtKB. DR GO; GO:0001525; P:angiogenesis; IDA:UniProtKB. DR GO; GO:0019731; P:antibacterial humoral response; IBA:GO_Central. DR GO; GO:0061844; P:antimicrobial humoral immune response mediated by antimicrobial peptide; IBA:GO_Central. DR GO; GO:0007154; P:cell communication; NAS:UniProtKB. DR GO; GO:0016477; P:cell migration; IMP:UniProtKB. DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IBA:GO_Central. DR GO; GO:0071425; P:hematopoietic stem cell proliferation; IDA:UniProtKB. DR GO; GO:0042592; P:homeostatic process; NAS:UniProtKB. DR GO; GO:0045087; P:innate immune response; IBA:GO_Central. DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB. DR GO; GO:0048662; P:negative regulation of smooth muscle cell proliferation; IDA:UniProtKB. DR GO; GO:0032055; P:negative regulation of translation in response to stress; IDA:UniProtKB. DR GO; GO:0001556; P:oocyte maturation; NAS:UniProtKB. DR GO; GO:0001541; P:ovarian follicle development; NAS:UniProtKB. DR GO; GO:0001890; P:placenta development; NAS:UniProtKB. DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IDA:UniProtKB. DR GO; GO:0042327; P:positive regulation of phosphorylation; IDA:UniProtKB. DR GO; GO:0050714; P:positive regulation of protein secretion; IDA:UniProtKB. DR GO; GO:0009725; P:response to hormone; IDA:UniProtKB. DR GO; GO:0001666; P:response to hypoxia; IDA:UniProtKB. DR GO; GO:0009303; P:rRNA transcription; IDA:UniProtKB. DR GO; GO:0007165; P:signal transduction; IDA:UniProt. DR GO; GO:0023052; P:signaling; IDA:UniProtKB. DR GO; GO:0034063; P:stress granule assembly; IDA:UniProtKB. DR GO; GO:0016078; P:tRNA decay; TAS:Reactome. DR CDD; cd06265; RNase_A_canonical; 1. DR FunFam; 3.10.130.10:FF:000001; Ribonuclease pancreatic; 1. DR Gene3D; 3.10.130.10; Ribonuclease A-like domain; 1. DR InterPro; IPR001427; RNaseA. DR InterPro; IPR036816; RNaseA-like_dom_sf. DR InterPro; IPR023411; RNaseA_AS. DR InterPro; IPR023412; RNaseA_domain. DR PANTHER; PTHR11437:SF60; ANGIOGENIN; 1. DR PANTHER; PTHR11437; RIBONUCLEASE; 1. DR Pfam; PF00074; RnaseA; 1. DR PRINTS; PR00794; RIBONUCLEASE. DR SMART; SM00092; RNAse_Pc; 1. DR SUPFAM; SSF54076; RNase A-like; 1. DR PROSITE; PS00127; RNASE_PANCREATIC; 1. PE 1: Evidence at protein level; KW 3D-structure; Amyotrophic lateral sclerosis; Angiogenesis; Cytoplasm; KW Developmental protein; Differentiation; Direct protein sequencing; KW Disease variant; Disulfide bond; DNA-binding; Endonuclease; Hydrolase; KW Neurodegeneration; Nuclease; Nucleus; Protein synthesis inhibitor; KW Proteomics identification; Pyrrolidone carboxylic acid; Reference proteome; KW Secreted; Signal; Stress response. FT SIGNAL 1..24 FT /evidence="ECO:0000269|PubMed:2866794" FT CHAIN 25..147 FT /note="Angiogenin" FT /evidence="ECO:0000269|PubMed:2866794, FT ECO:0000269|PubMed:2866795" FT /id="PRO_0000030843" FT MOTIF 55..59 FT /note="Nucleolar localization signal" FT /evidence="ECO:0000269|PubMed:7945327" FT ACT_SITE 37 FT /note="Proton acceptor" FT /evidence="ECO:0000269|PubMed:11468363, FT ECO:0000269|PubMed:38718836, ECO:0000269|PubMed:9918722" FT ACT_SITE 138 FT /note="Proton donor" FT /evidence="ECO:0000269|PubMed:11468363, FT ECO:0000269|PubMed:38718836, ECO:0000269|PubMed:9918722" FT BINDING 45 FT /ligand="tRNA" FT /ligand_id="ChEBI:CHEBI:17843" FT /evidence="ECO:0000269|PubMed:38718836" FT BINDING 46 FT /ligand="tRNA" FT /ligand_id="ChEBI:CHEBI:17843" FT /evidence="ECO:0000269|PubMed:38718836" FT BINDING 105 FT /ligand="tRNA" FT /ligand_id="ChEBI:CHEBI:17843" FT /evidence="ECO:0000269|PubMed:38718836" FT BINDING 127 FT /ligand="tRNA" FT /ligand_id="ChEBI:CHEBI:17843" FT /evidence="ECO:0000269|PubMed:38718836" FT MOD_RES 25 FT /note="Pyrrolidone carboxylic acid" FT /evidence="ECO:0000269|PubMed:2866794" FT DISULFID 50..105 FT /evidence="ECO:0000269|PubMed:11468363, FT ECO:0000269|PubMed:11851402, ECO:0000269|PubMed:12842050, FT ECO:0000269|PubMed:14756559, ECO:0000269|PubMed:28176817, FT ECO:0000269|PubMed:2866794, ECO:0000269|PubMed:37218877, FT ECO:0000269|PubMed:38718836, ECO:0000269|PubMed:8159679, FT ECO:0000269|PubMed:9311977, ECO:0000269|PubMed:9461294, FT ECO:0000269|PubMed:9918722, ECO:0007744|PDB:1A4Y, FT ECO:0007744|PDB:1ANG, ECO:0007744|PDB:1AWZ, FT ECO:0007744|PDB:1B1E, ECO:0007744|PDB:1B1I, FT ECO:0007744|PDB:1B1J, ECO:0007744|PDB:1H0D, FT ECO:0007744|PDB:1H52, ECO:0007744|PDB:1H53, FT ECO:0007744|PDB:1HBY, ECO:0007744|PDB:1K58, FT ECO:0007744|PDB:1K59, ECO:0007744|PDB:1K5A, FT ECO:0007744|PDB:1K5B, ECO:0007744|PDB:1UN3, FT ECO:0007744|PDB:1UN4, ECO:0007744|PDB:1UN5, FT ECO:0007744|PDB:2ANG, ECO:0007744|PDB:4AHD, FT ECO:0007744|PDB:4AHE, ECO:0007744|PDB:4AHF, FT ECO:0007744|PDB:4AHG, ECO:0007744|PDB:4AHH, FT ECO:0007744|PDB:4AHI, ECO:0007744|PDB:4AHJ, FT ECO:0007744|PDB:4AHK, ECO:0007744|PDB:4AHL, FT ECO:0007744|PDB:4AHM, ECO:0007744|PDB:4AHN, FT ECO:0007744|PDB:4AOH, ECO:0007744|PDB:4B36, FT ECO:0007744|PDB:5EOP, ECO:0007744|PDB:5EPZ, FT ECO:0007744|PDB:5EQO, ECO:0007744|PDB:5M9A, FT ECO:0007744|PDB:5M9C, ECO:0007744|PDB:5M9G, FT ECO:0007744|PDB:5M9J, ECO:0007744|PDB:5M9M, FT ECO:0007744|PDB:5M9P, ECO:0007744|PDB:5M9Q, FT ECO:0007744|PDB:5M9R, ECO:0007744|PDB:5M9S, FT ECO:0007744|PDB:5M9T, ECO:0007744|PDB:5M9V, FT ECO:0007744|PDB:7NPM, ECO:0007744|PDB:7PNJ, FT ECO:0007744|PDB:7PNP, ECO:0007744|PDB:7PNR, FT ECO:0007744|PDB:8AF0" FT DISULFID 63..116 FT /evidence="ECO:0000269|PubMed:11468363, FT ECO:0000269|PubMed:11851402, ECO:0000269|PubMed:12842050, FT ECO:0000269|PubMed:14756559, ECO:0000269|PubMed:28176817, FT ECO:0000269|PubMed:2866794, ECO:0000269|PubMed:37218877, FT ECO:0000269|PubMed:38718836, ECO:0000269|PubMed:8159679, FT ECO:0000269|PubMed:9311977, ECO:0000269|PubMed:9461294, FT ECO:0000269|PubMed:9918722, ECO:0007744|PDB:1A4Y, FT ECO:0007744|PDB:1ANG, ECO:0007744|PDB:1AWZ, FT ECO:0007744|PDB:1B1E, ECO:0007744|PDB:1B1I, FT ECO:0007744|PDB:1B1J, ECO:0007744|PDB:1H0D, FT ECO:0007744|PDB:1H52, ECO:0007744|PDB:1H53, FT ECO:0007744|PDB:1HBY, ECO:0007744|PDB:1K58, FT ECO:0007744|PDB:1K59, ECO:0007744|PDB:1K5A, FT ECO:0007744|PDB:1K5B, ECO:0007744|PDB:1UN3, FT ECO:0007744|PDB:1UN4, ECO:0007744|PDB:1UN5, FT ECO:0007744|PDB:2ANG, ECO:0007744|PDB:4AHD, FT ECO:0007744|PDB:4AHE, ECO:0007744|PDB:4AHF, FT ECO:0007744|PDB:4AHG, ECO:0007744|PDB:4AHH, FT ECO:0007744|PDB:4AHI, ECO:0007744|PDB:4AHJ, FT ECO:0007744|PDB:4AHK, ECO:0007744|PDB:4AHL, FT ECO:0007744|PDB:4AHM, ECO:0007744|PDB:4AHN, FT ECO:0007744|PDB:4AOH, ECO:0007744|PDB:4B36, FT ECO:0007744|PDB:5EOP, ECO:0007744|PDB:5EPZ, FT ECO:0007744|PDB:5EQO, ECO:0007744|PDB:5M9A, FT ECO:0007744|PDB:5M9C, ECO:0007744|PDB:5M9G, FT ECO:0007744|PDB:5M9J, ECO:0007744|PDB:5M9M, FT ECO:0007744|PDB:5M9P, ECO:0007744|PDB:5M9Q, FT ECO:0007744|PDB:5M9R, ECO:0007744|PDB:5M9S, FT ECO:0007744|PDB:5M9T, ECO:0007744|PDB:5M9V, FT ECO:0007744|PDB:7NPM, ECO:0007744|PDB:7PNJ, FT ECO:0007744|PDB:7PNP, ECO:0007744|PDB:7PNR, FT ECO:0007744|PDB:8AF0" FT DISULFID 81..131 FT /evidence="ECO:0000269|PubMed:11468363, FT ECO:0000269|PubMed:11851402, ECO:0000269|PubMed:12842050, FT ECO:0000269|PubMed:14756559, ECO:0000269|PubMed:28176817, FT ECO:0000269|PubMed:2866794, ECO:0000269|PubMed:37218877, FT ECO:0000269|PubMed:38718836, ECO:0000269|PubMed:8159679, FT ECO:0000269|PubMed:9311977, ECO:0000269|PubMed:9461294, FT ECO:0000269|PubMed:9918722, ECO:0007744|PDB:1A4Y, FT ECO:0007744|PDB:1ANG, ECO:0007744|PDB:1AWZ, FT ECO:0007744|PDB:1B1E, ECO:0007744|PDB:1B1I, FT ECO:0007744|PDB:1B1J, ECO:0007744|PDB:1H0D, FT ECO:0007744|PDB:1H52, ECO:0007744|PDB:1H53, FT ECO:0007744|PDB:1HBY, ECO:0007744|PDB:1K58, FT ECO:0007744|PDB:1K59, ECO:0007744|PDB:1K5A, FT ECO:0007744|PDB:1K5B, ECO:0007744|PDB:1UN3, FT ECO:0007744|PDB:1UN4, ECO:0007744|PDB:1UN5, FT ECO:0007744|PDB:2ANG, ECO:0007744|PDB:4AHD, FT ECO:0007744|PDB:4AHE, ECO:0007744|PDB:4AHF, FT ECO:0007744|PDB:4AHG, ECO:0007744|PDB:4AHH, FT ECO:0007744|PDB:4AHI, ECO:0007744|PDB:4AHJ, FT ECO:0007744|PDB:4AHK, ECO:0007744|PDB:4AHL, FT ECO:0007744|PDB:4AHM, ECO:0007744|PDB:4AHN, FT ECO:0007744|PDB:4AOH, ECO:0007744|PDB:4B36, FT ECO:0007744|PDB:5EOP, ECO:0007744|PDB:5EPZ, FT ECO:0007744|PDB:5EQO, ECO:0007744|PDB:5M9A, FT ECO:0007744|PDB:5M9C, ECO:0007744|PDB:5M9G, FT ECO:0007744|PDB:5M9J, ECO:0007744|PDB:5M9M, FT ECO:0007744|PDB:5M9P, ECO:0007744|PDB:5M9Q, FT ECO:0007744|PDB:5M9R, ECO:0007744|PDB:5M9S, FT ECO:0007744|PDB:5M9T, ECO:0007744|PDB:5M9V, FT ECO:0007744|PDB:7NPM, ECO:0007744|PDB:7PNJ, FT ECO:0007744|PDB:7PNP, ECO:0007744|PDB:7PNR, FT ECO:0007744|PDB:8AF0" FT VARIANT 12 FT /note="F -> L (in ALS9)" FT /evidence="ECO:0000269|PubMed:19363631, FT ECO:0000269|PubMed:22190368" FT /id="VAR_089762" FT VARIANT 12 FT /note="F -> S (in ALS9)" FT /evidence="ECO:0000269|PubMed:18087731, FT ECO:0000269|PubMed:22190368" FT /id="VAR_044145" FT VARIANT 13 FT /note="V -> A (found in a patient with Parkinson disease; FT uncertain significance)" FT /evidence="ECO:0000269|PubMed:22190368" FT /id="VAR_089763" FT VARIANT 15 FT /note="G -> D (in ALS9; uncertain significance)" FT /evidence="ECO:0000269|PubMed:22190368" FT /id="VAR_089764" FT VARIANT 17 FT /note="G -> D (found in a patient with Parkinson disease; FT uncertain significance)" FT /evidence="ECO:0000269|PubMed:22190368" FT /id="VAR_089765" FT VARIANT 20 FT /note="P -> Q (in ALS9; uncertain significance)" FT /evidence="ECO:0000269|PubMed:22190368" FT /id="VAR_089766" FT VARIANT 20 FT /note="P -> S (in ALS9)" FT /evidence="ECO:0000269|PubMed:17886298, FT ECO:0000269|PubMed:18087731, ECO:0000269|PubMed:22190368" FT /id="VAR_044146" FT VARIANT 36 FT /note="Q -> L (in ALS9; reduced ribonucleolytic activity; FT low angiogenic activity; reduced mitogenic activity; wild FT type far-UV CD spectra; dbSNP:rs121909535)" FT /evidence="ECO:0000269|PubMed:16501576, FT ECO:0000269|PubMed:17900154, ECO:0000269|PubMed:22190368" FT /id="VAR_044147" FT VARIANT 37 FT /note="H -> R (found in a patient with Parkinson disease; FT uncertain significance)" FT /evidence="ECO:0000269|PubMed:22190368" FT /id="VAR_089767" FT VARIANT 38 FT /note="Y -> H (in ALS9; dbSNP:rs1032422334)" FT /evidence="ECO:0000269|PubMed:22292843" FT /id="VAR_073021" FT VARIANT 41 FT /note="K -> E (in ALS9; reduced ribonucleolytic activity; FT dbSNP:rs121909537)" FT /evidence="ECO:0000269|PubMed:16501576, FT ECO:0000269|PubMed:17900154, ECO:0000269|PubMed:19153377, FT ECO:0000269|PubMed:22190368" FT /id="VAR_044148" FT VARIANT 41 FT /note="K -> I (in ALS9; loss of angiogenic activity; FT reduced ribonucleolytic activity; retains nuclear FT translocation; dbSNP:rs121909536)" FT /evidence="ECO:0000269|PubMed:16501576, FT ECO:0000269|PubMed:17886298, ECO:0000269|PubMed:17900154, FT ECO:0000269|PubMed:22292843" FT /id="VAR_044149" FT VARIANT 46 FT /note="D -> G (in ALS9; homodimerization is similar to FT wild-type; localization in the nucleus is similar to the FT wild-type; strongly reduces ribonucleolytic activity; FT dbSNP:rs1440927797)" FT /evidence="ECO:0000269|PubMed:22292843, FT ECO:0000269|PubMed:25372031" FT /id="VAR_073022" FT VARIANT 46 FT /note="D -> V (found in a patient with Parkinson disease; FT uncertain significance)" FT /evidence="ECO:0000269|PubMed:22190368" FT /id="VAR_089768" FT VARIANT 52 FT /note="S -> N (in ALS9; loss of angiogenic activity; FT reduced ribonucleolytic activity; unable to translocate to FT the nucleus; dbSNP:rs121909542)" FT /evidence="ECO:0000269|PubMed:17886298, FT ECO:0000269|PubMed:22190368" FT /id="VAR_044150" FT VARIANT 55 FT /note="R -> K (in ALS9; marginally reduced ribonucleolytic FT activity; wild type far-UV CD spectra; dbSNP:rs121909538)" FT /evidence="ECO:0000269|PubMed:16501576, FT ECO:0000269|PubMed:17900154, ECO:0000269|PubMed:22190368" FT /id="VAR_044151" FT VARIANT 63 FT /note="C -> W (in ALS9; reduced ribonucleolytic activity; FT low angiogenic activity; reduced mitogenic activity; FT reduced thermal stability; dbSNP:rs121909539)" FT /evidence="ECO:0000269|PubMed:16501576, FT ECO:0000269|PubMed:17900154, ECO:0000269|PubMed:22190368" FT /id="VAR_044152" FT VARIANT 64 FT /note="K -> E (in ALS9; uncertain significance)" FT /evidence="ECO:0000269|PubMed:22190368" FT /id="VAR_089769" FT VARIANT 64 FT /note="K -> I (in ALS9; reduced ribonucleolytic activity; FT low angiogenic activity; reduced mitogenic activity; FT moderate reduction of thermal stability; FT dbSNP:rs121909540)" FT /evidence="ECO:0000269|PubMed:15557516, FT ECO:0000269|PubMed:16501576, ECO:0000269|PubMed:17900154, FT ECO:0000269|PubMed:22190368" FT /id="VAR_044153" FT VARIANT 70 FT /note="I -> V (in ALS9; uncertain significance; reduced FT ribonucleolytic activity; moderate reduction of thermal FT stability; dbSNP:rs121909541)" FT /evidence="ECO:0000269|PubMed:16501576, FT ECO:0000269|PubMed:17900154, ECO:0000269|PubMed:18087731, FT ECO:0000269|PubMed:18852347" FT /id="VAR_044154" FT VARIANT 78 FT /note="K -> E (in ALS9; decreased interaction with the FT ribosome and ability to repress translation)" FT /evidence="ECO:0000269|PubMed:19363631, FT ECO:0000269|PubMed:38718836" FT /id="VAR_089770" FT VARIANT 78 FT /note="K -> R (found in a patient with Parkinson disease; FT uncertain significance)" FT /evidence="ECO:0000269|PubMed:22190368" FT /id="VAR_089771" FT VARIANT 84 FT /note="K -> E (in dbSNP:rs17560)" FT /evidence="ECO:0000269|PubMed:11919285" FT /id="VAR_013148" FT VARIANT 104 FT /note="T -> S (in ALS9; uncertain significance)" FT /evidence="ECO:0000269|PubMed:22190368" FT /id="VAR_089772" FT VARIANT 119 FT /note="R -> Q (found in a patient with Parkinson disease; FT uncertain significance)" FT /evidence="ECO:0000269|PubMed:22190368" FT /id="VAR_089773" FT VARIANT 124 FT /note="F -> I (in ALS9; uncertain significance)" FT /evidence="ECO:0000269|PubMed:22190368" FT /id="VAR_089774" FT VARIANT 127 FT /note="V -> I (in ALS9; uncertain significance)" FT /evidence="ECO:0000269|PubMed:22292798" FT /id="VAR_089775" FT VARIANT 136 FT /note="P -> L (in ALS9; loss of angiogenic activity; FT reduced tRNA ribonucleolytic activity; unable to FT translocate to the nucleus; dbSNP:rs121909543)" FT /evidence="ECO:0000269|PubMed:17886298, FT ECO:0000269|PubMed:19332886, ECO:0000269|PubMed:22190368, FT ECO:0000269|PubMed:29748193" FT /id="VAR_044155" FT VARIANT 137 FT /note="V -> I (in ALS9; dbSNP:rs121909544)" FT /evidence="ECO:0000269|PubMed:18087731, FT ECO:0000269|PubMed:22190368" FT /id="VAR_044156" FT VARIANT 138 FT /note="H -> R (in ALS9; uncertain significance)" FT /evidence="ECO:0000269|PubMed:18087731, FT ECO:0000269|PubMed:22190368" FT /id="VAR_044157" FT VARIANT 145 FT /note="R -> C (found in a patient with Parkinson disease)" FT /evidence="ECO:0000269|PubMed:22190368" FT /id="VAR_089776" FT VARIANT 145 FT /note="R -> H (in ALS9; uncertain significance)" FT /evidence="ECO:0000269|PubMed:18852347, FT ECO:0000269|PubMed:22190368" FT /id="VAR_089777" FT MUTAGEN 29 FT /note="R->A: Affects substrate preference. Significantly FT decreases binding affinity for RNH1." FT /evidence="ECO:0000269|PubMed:10413501, FT ECO:0000269|PubMed:8570639" FT MUTAGEN 32 FT /note="H->A: Significantly decreases binding affinity for FT RNH1." FT /evidence="ECO:0000269|PubMed:9050852" FT MUTAGEN 36 FT /note="Q->A: Slightly decreases binding affinity for RNH1." FT /evidence="ECO:0000269|PubMed:9050852" FT MUTAGEN 37 FT /note="H->A: Abolished ribonuclease activity. does not FT affect binding to PLXNB2 receptor." FT /evidence="ECO:0000269|PubMed:29100074, FT ECO:0000269|PubMed:38718836" FT MUTAGEN 59 FT /note="L->P: Homodimerization is similar to wild-type; FT causes mislocalization in the cytoplasm; strongly reduces FT ribonucleolytic activity." FT /evidence="ECO:0000269|PubMed:25372031" FT MUTAGEN 64 FT /note="K->Q: Significantly decreases binding affinity for FT RNH1." FT /evidence="ECO:0000269|PubMed:10413501, FT ECO:0000269|PubMed:9050852" FT MUTAGEN 68 FT /note="T->A: Decreased ribonuclease activity." FT /evidence="ECO:0000269|PubMed:9578571" FT MUTAGEN 90 FT /note="R->A: Abolished binding to PLXNB2 receptor." FT /evidence="ECO:0000269|PubMed:29100074" FT MUTAGEN 92 FT /note="N->A: Slightly decreases binding affinity for RNH1." FT /evidence="ECO:0000269|PubMed:9050852" FT MUTAGEN 92 FT /note="N->D: Abolished binding to PLXNB2 receptor." FT /evidence="ECO:0000269|PubMed:29100074" FT MUTAGEN 104 FT /note="T->A: Increased ribonuclease activity." FT /evidence="ECO:0000269|PubMed:9578571" FT MUTAGEN 104 FT /note="T->D: Slightly increased ribonuclease activity." FT /evidence="ECO:0000269|PubMed:9578571" FT MUTAGEN 109..110 FT /note="GG->RR: Significantly decreases binding affinity for FT RNH1." FT /evidence="ECO:0000269|PubMed:19354288" FT MUTAGEN 132 FT /note="E->A: Slightly decreases binding affinity for RNH1." FT /evidence="ECO:0000269|PubMed:9050852" FT MUTAGEN 140..141 FT /note="DQ->AA: Slightly increased ribonuclease activity." FT /evidence="ECO:0000269|PubMed:8159680" FT MUTAGEN 140 FT /note="D->N,H,S,A: Strongly increased ribonuclease FT activity." FT /evidence="ECO:0000269|PubMed:11851402, FT ECO:0000269|PubMed:2459697" FT MUTAGEN 141 FT /note="Q->A,G: Strongly increased ribonuclease activity." FT /evidence="ECO:0000269|PubMed:11851402, FT ECO:0000269|PubMed:8159680" FT MUTAGEN 143..144 FT /note="IF->AA: Increased ribonuclease activity." FT /evidence="ECO:0000269|PubMed:11851402, FT ECO:0000269|PubMed:8622921" FT HELIX 28..37 FT /evidence="ECO:0007829|PDB:4AOH" FT HELIX 47..56 FT /evidence="ECO:0007829|PDB:4AOH" FT TURN 60..63 FT /evidence="ECO:0007829|PDB:4AOH" FT STRAND 65..70 FT /evidence="ECO:0007829|PDB:4AOH" FT HELIX 74..78 FT /evidence="ECO:0007829|PDB:4AOH" FT HELIX 79..81 FT /evidence="ECO:0007829|PDB:4AOH" FT TURN 83..85 FT /evidence="ECO:0007829|PDB:4AOH" FT STRAND 86..89 FT /evidence="ECO:0007829|PDB:4AOH" FT TURN 90..92 FT /evidence="ECO:0007829|PDB:4AOH" FT STRAND 93..98 FT /evidence="ECO:0007829|PDB:4AOH" FT STRAND 100..110 FT /evidence="ECO:0007829|PDB:4AOH" FT STRAND 112..115 FT /evidence="ECO:0007829|PDB:4AOH" FT STRAND 117..125 FT /evidence="ECO:0007829|PDB:4AOH" FT STRAND 128..132 FT /evidence="ECO:0007829|PDB:4AOH" FT STRAND 135..139 FT /evidence="ECO:0007829|PDB:4AOH" FT HELIX 141..144 FT /evidence="ECO:0007829|PDB:4AOH" SQ SEQUENCE 147 AA; 16550 MW; 9C462DA3C8D39ACC CRC64; MVMGLGVLLL VFVLGLGLTP PTLAQDNSRY THFLTQHYDA KPQGRDDRYC ESIMRRRGLT SPCKDINTFI HGNKRSIKAI CENKNGNPHR ENLRISKSSF QVTTCKLHGG SPWPPCQYRA TAGFRNVVVA CENGLPVHLD QSIFRRP // ID ATX2_HUMAN Reviewed; 1313 AA. AC Q99700; A6NLD4; Q24JQ7; Q6ZQZ7; Q99493; DT 13-SEP-2004, integrated into UniProtKB/Swiss-Prot. DT 25-NOV-2008, sequence version 2. DT 28-JAN-2026, entry version 204. DE RecName: Full=Ataxin-2; DE AltName: Full=Spinocerebellar ataxia type 2 protein; DE AltName: Full=Trinucleotide repeat-containing gene 13 protein; GN Name=ATXN2; Synonyms=ATX2, SCA2, TNRC13; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), POLYMORPHISM, INVOLVEMENT IN SCA2, RP TISSUE SPECIFICITY, AND VARIANT VAL-107. RX PubMed=8896555; DOI=10.1038/ng1196-269; RA Pulst S.-M., Nechiporuk A., Nechiporuk T., Gispert S., Chen X.-N., RA Lopes-Cendes I., Pearlman S., Starkman S., Orozco-Diaz G., Lunkes A., RA DeJong P., Rouleau G.A., Auburger G., Korenberg J.R., Figueroa C., RA Sahba S.; RT "Moderate expansion of a normally biallelic trinucleotide repeat in RT spinocerebellar ataxia type 2."; RL Nat. Genet. 14:269-276(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), POLYMORPHISM, INVOLVEMENT IN SCA2, RP AND TISSUE SPECIFICITY. RX PubMed=8896556; DOI=10.1038/ng1196-277; RA Sanpei K., Takano H., Igarashi S., Sato T., Oyake M., Sasaki H., RA Wakisaka A., Tashiro K., Ishida Y., Ikeuchi T., Koide R., Saito M., RA Sato A., Tanaka T., Hanyu S., Takiyama Y., Nishizawa M., Shimizu N., RA Nomura Y., Segawa M., Iwabuchi K., Eguchi I., Tanaka H., Takahashi H., RA Tsuji S.; RT "Identification of the spinocerebellar ataxia type 2 gene using a direct RT identification of repeat expansion and cloning technique, DIRECT."; RL Nat. Genet. 14:277-284(1996). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16541075; DOI=10.1038/nature04569; RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., RA Gibbs R.A.; RT "The finished DNA sequence of human chromosome 12."; RL Nature 440:346-351(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5). RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 81-1313 (ISOFORM 2), POLYMORPHISM, RP INVOLVEMENT IN SCA2, TISSUE SPECIFICITY, AND VARIANT VAL-107. RX PubMed=8896557; DOI=10.1038/ng1196-285; RA Imbert G., Saudou F., Yvert G., Devys D., Trottier Y., Garnier J.-M., RA Weber C., Mandel J.-L., Cancel G., Abbas N., Duerr A., Didierjean O., RA Stevanin G., Agid Y., Brice A.; RT "Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high RT sensitivity to expanded CAG/glutamine repeats."; RL Nat. Genet. 14:285-291(1996). RN [7] RP ALTERNATIVE SPLICING, AND TISSUE SPECIFICITY. RX PubMed=9480749; DOI=10.1006/geno.1997.5131; RA Sahba S., Nechiporuk A., Figueroa K.P., Nechiporuk T., Pulst S.-M.; RT "Genomic structure of the human gene for spinocerebellar ataxia type 2 RT (SCA2) on chromosome 12q24.1."; RL Genomics 47:359-364(1998). RN [8] RP INTERACTION WITH RBFOX1. RX PubMed=10814712; DOI=10.1093/hmg/9.9.1303; RA Shibata H., Huynh D.P., Pulst S.-M.; RT "A novel protein with RNA-binding motifs interacts with ataxin-2."; RL Hum. Mol. Genet. 9:1303-1313(2000). RN [9] RP INTERACTION WITH POLYRIBOSOMES. RX PubMed=16835262; DOI=10.1093/hmg/ddl173; RA Satterfield T.F., Pallanck L.J.; RT "Ataxin-2 and its Drosophila homolog, ATX2, physically assemble with RT polyribosomes."; RL Hum. Mol. Genet. 15:2523-2532(2006). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein phosphorylation RT analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [11] RP FUNCTION, AND INTERACTION WITH EGFR; SH3GL2 AND SH3GL3. RX PubMed=18602463; DOI=10.1016/j.cellsig.2008.05.018; RA Nonis D., Schmidt M.H., van de Loo S., Eich F., Dikic I., Nowock J., RA Auburger G.; RT "Ataxin-2 associates with the endocytosis complex and affects EGF receptor RT trafficking."; RL Cell. Signal. 20:1725-1739(2008). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-784, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18220336; DOI=10.1021/pr0705441; RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III; RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient RT phosphoproteomic analysis."; RL J. Proteome Res. 7:1346-1351(2008). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-466; SER-554; SER-684; RP THR-741; SER-857; SER-861; SER-888 AND SER-889, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-684, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [16] RP INTERACTION WITH TARDBP, INVOLVEMENT IN ALS13, AND POLY-GLN REPEAT RP EXPANSION. RX PubMed=20740007; DOI=10.1038/nature09320; RA Elden A.C., Kim H.J., Hart M.P., Chen-Plotkin A.S., Johnson B.S., Fang X., RA Armakola M., Geser F., Greene R., Lu M.M., Padmanabhan A., Clay-Falcone D., RA McCluskey L., Elman L., Juhr D., Gruber P.J., Rub U., Auburger G., RA Trojanowski J.Q., Lee V.M., Van Deerlin V.M., Bonini N.M., Gitler A.D.; RT "Ataxin-2 intermediate-length polyglutamine expansions are associated with RT increased risk for ALS."; RL Nature 466:1069-1075(2010). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-393; SER-684 AND SER-784, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-784; SER-861 AND SER-865, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [20] RP INTERACTION WITH ATXN2L. RX PubMed=23209657; DOI=10.1371/journal.pone.0050134; RA Kaehler C., Isensee J., Nonhoff U., Terrey M., Hucho T., Lehrach H., RA Krobitsch S.; RT "Ataxin-2-like is a regulator of stress granules and processing bodies."; RL PLoS ONE 7:E50134-E50134(2012). RN [21] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-466; SER-478; SER-508; RP SER-624; SER-642; SER-684; SER-772; SER-784 AND SER-889, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-624 AND SER-728, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [23] RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-640, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Colon carcinoma; RX PubMed=24129315; DOI=10.1074/mcp.o113.027870; RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M., RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V., RA Bedford M.T., Comb M.J.; RT "Immunoaffinity enrichment and mass spectrometry analysis of protein RT methylation."; RL Mol. Cell. Proteomics 13:372-387(2014). RN [24] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-893, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). CC -!- FUNCTION: Involved in EGFR trafficking, acting as negative regulator of CC endocytic EGFR internalization at the plasma membrane. CC {ECO:0000269|PubMed:18602463}. CC -!- SUBUNIT: Monomer (By similarity). Can also form homodimers (By CC similarity). Interacts with TARDBP; the interaction is RNA-dependent CC (PubMed:20740007). Interacts with RBFOX1 (PubMed:10814712). Interacts CC with polyribosomes (PubMed:16835262). Interacts with SH3GL2 and SH3GL3 CC (PubMed:18602463). Interacts with SH3KBP1 and CBL (By similarity). CC Interacts with EGFR (PubMed:18602463). Interacts with ATXN2L CC (PubMed:23209657). {ECO:0000250|UniProtKB:O70305, CC ECO:0000269|PubMed:10814712, ECO:0000269|PubMed:16835262, CC ECO:0000269|PubMed:18602463, ECO:0000269|PubMed:20740007, CC ECO:0000269|PubMed:23209657}. CC -!- INTERACTION: CC Q99700; P54253: ATXN1; NbExp=4; IntAct=EBI-697691, EBI-930964; CC Q99700; P26196: DDX6; NbExp=14; IntAct=EBI-697691, EBI-351257; CC Q99700; Q13283: G3BP1; NbExp=4; IntAct=EBI-697691, EBI-1047359; CC Q99700; P11940: PABPC1; NbExp=8; IntAct=EBI-697691, EBI-81531; CC Q99700; Q99962: SH3GL2; NbExp=9; IntAct=EBI-697691, EBI-77938; CC Q99700; Q99963: SH3GL3; NbExp=11; IntAct=EBI-697691, EBI-473910; CC Q99700; Q13148: TARDBP; NbExp=3; IntAct=EBI-697691, EBI-372899; CC Q99700-5; P54253: ATXN1; NbExp=6; IntAct=EBI-25891409, EBI-930964; CC Q99700-5; P46379-2: BAG6; NbExp=3; IntAct=EBI-25891409, EBI-10988864; CC Q99700-5; Q9BTH3: BIN1; NbExp=3; IntAct=EBI-25891409, EBI-25891390; CC Q99700-5; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-25891409, EBI-2837444; CC Q99700-5; P20963: CD247; NbExp=3; IntAct=EBI-25891409, EBI-1165705; CC Q99700-5; P11940: PABPC1; NbExp=3; IntAct=EBI-25891409, EBI-81531; CC Q99700-5; Q9NWB1-5: RBFOX1; NbExp=3; IntAct=EBI-25891409, EBI-12123390; CC Q99700-5; Q8IVP1: SH3GL3; NbExp=3; IntAct=EBI-25891409, EBI-6503765; CC Q99700-5; Q9UJZ1: STOML2; NbExp=3; IntAct=EBI-25891409, EBI-1044428; CC Q99700-5; P55854: SUMO3; NbExp=3; IntAct=EBI-25891409, EBI-474067; CC Q99700-5; P40337-2: VHL; NbExp=3; IntAct=EBI-25891409, EBI-12157263; CC Q99700-5; Q96E88; NbExp=3; IntAct=EBI-25891409, EBI-10976904; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=5; CC Name=1; CC IsoId=Q99700-1; Sequence=Displayed; CC Name=2; CC IsoId=Q99700-2; Sequence=VSP_011575, VSP_011577; CC Name=3; CC IsoId=Q99700-3; Sequence=VSP_011574, VSP_011576, VSP_011578, CC VSP_011579, VSP_011580, VSP_011581; CC Name=4; CC IsoId=Q99700-4; Sequence=VSP_011582; CC Name=5; CC IsoId=Q99700-5; Sequence=VSP_057285, VSP_057286, VSP_057287; CC -!- TISSUE SPECIFICITY: Expressed in the brain, heart, liver, skeletal CC muscle, pancreas and placenta. Isoform 1 is predominant in the brain CC and spinal cord. Isoform 4 is more abundant in the cerebellum. In the CC brain, broadly expressed in the amygdala, caudate nucleus, corpus CC callosum, hippocampus, hypothalamus, substantia nigra, subthalamic CC nucleus and thalamus. {ECO:0000269|PubMed:8896555, CC ECO:0000269|PubMed:8896556, ECO:0000269|PubMed:8896557, CC ECO:0000269|PubMed:9480749}. CC -!- POLYMORPHISM: The poly-Gln region of ATXN2 is polymorphic: 17 to 29 CC repeats are found in the normal population. Higher numbers of repeats CC result in different disease phenotypes depending on the length of the CC expansion. {ECO:0000269|PubMed:20740007, ECO:0000269|PubMed:8896555, CC ECO:0000269|PubMed:8896556, ECO:0000269|PubMed:8896557}. CC -!- DISEASE: Spinocerebellar ataxia 2 (SCA2) [MIM:183090]: Spinocerebellar CC ataxia is a clinically and genetically heterogeneous group of CC cerebellar disorders. Patients show progressive incoordination of gait CC and often poor coordination of hands, speech and eye movements, due to CC cerebellum degeneration with variable involvement of the brainstem and CC spinal cord. SCA2 belongs to the autosomal dominant cerebellar ataxias CC type I (ADCA I) which are characterized by cerebellar ataxia in CC combination with additional clinical features like optic atrophy, CC ophthalmoplegia, bulbar and extrapyramidal signs, peripheral neuropathy CC and dementia. SCA2 is characterized by hyporeflexia, myoclonus and CC action tremor and dopamine-responsive parkinsonism. In some patients, CC SCA2 presents as pure familial parkinsonism without cerebellar signs. CC {ECO:0000269|PubMed:8896555, ECO:0000269|PubMed:8896556, CC ECO:0000269|PubMed:8896557}. Note=The disease is caused by variants CC affecting the gene represented in this entry. SCA2 is caused by CC expansion of a CAG repeat resulting in about 36 to 52 repeats in some CC patients. Longer expansions result in earlier the expansion, onset of CC the disease. CC -!- DISEASE: Amyotrophic lateral sclerosis 13 (ALS13) [MIM:183090]: A CC neurodegenerative disorder affecting upper motor neurons in the brain CC and lower motor neurons in the brain stem and spinal cord, resulting in CC fatal paralysis. Sensory abnormalities are absent. The pathologic CC hallmarks of the disease include pallor of the corticospinal tract due CC to loss of motor neurons, presence of ubiquitin-positive inclusions CC within surviving motor neurons, and deposition of pathologic CC aggregates. The etiology of amyotrophic lateral sclerosis is likely to CC be multifactorial, involving both genetic and environmental factors. CC The disease is inherited in 5-10% of the cases. CC {ECO:0000269|PubMed:20740007}. Note=Disease susceptibility is CC associated with variants affecting the gene represented in this entry. CC An increased risk for developing amyotrophic lateral sclerosis seems to CC be conferred by CAG repeat intermediate expansions greater than 23 but CC below the threshold for developing spinocerebellar ataxia. CC -!- SIMILARITY: Belongs to the ataxin-2 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U70323; AAB19200.1; -; mRNA. DR EMBL; AK128613; BAC87528.1; -; mRNA. DR EMBL; AC002395; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC137055; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; KF455720; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC114546; AAI14547.1; -; mRNA. DR EMBL; Y08262; CAA69589.1; -; mRNA. DR CCDS; CCDS81738.1; -. [Q99700-5] DR RefSeq; NP_001297052.1; NM_001310123.1. [Q99700-5] DR RefSeq; NP_002964.4; NM_002973.4. DR PDB; 3KTR; X-ray; 1.70 A; B=912-928. DR PDBsum; 3KTR; -. DR AlphaFoldDB; Q99700; -. DR SMR; Q99700; -. DR BioGRID; 112218; 327. DR DIP; DIP-33372N; -. DR ELM; Q99700; -. DR FunCoup; Q99700; 1901. DR IntAct; Q99700; 166. DR MINT; Q99700; -. DR STRING; 9606.ENSP00000446576; -. DR BindingDB; Q99700; -. DR ChEMBL; CHEMBL1795085; -. DR GlyCosmos; Q99700; 7 sites, 1 glycan. DR GlyGen; Q99700; 26 sites, 1 O-linked glycan (23 sites). DR iPTMnet; Q99700; -. DR MetOSite; Q99700; -. DR PhosphoSitePlus; Q99700; -. DR SwissPalm; Q99700; -. DR BioMuta; ATXN2; -. DR DMDM; 215273941; -. DR jPOST; Q99700; -. DR MassIVE; Q99700; -. DR PaxDb; 9606-ENSP00000366843; -. DR PeptideAtlas; Q99700; -. DR ProteomicsDB; 61268; -. DR ProteomicsDB; 78409; -. [Q99700-1] DR ProteomicsDB; 78410; -. [Q99700-2] DR ProteomicsDB; 78412; -. [Q99700-4] DR Pumba; Q99700; -. DR Antibodypedia; 18563; 277 antibodies from 36 providers. DR DNASU; 6311; -. DR Ensembl; ENST00000535949.5; ENSP00000439338.1; ENSG00000204842.19. [Q99700-5] DR Ensembl; ENST00000550104.5; ENSP00000446576.2; ENSG00000204842.19. [Q99700-1] DR Ensembl; ENST00000616825.4; ENSP00000481448.1; ENSG00000204842.19. [Q99700-5] DR GeneID; 6311; -. DR KEGG; hsa:6311; -. DR UCSC; uc001tsj.3; human. [Q99700-1] DR AGR; HGNC:10555; -. DR ClinPGx; PA34968; -. DR CTD; 6311; -. DR DisGeNET; 6311; -. DR GeneCards; ATXN2; -. DR GeneReviews; ATXN2; -. DR HGNC; HGNC:10555; ATXN2. DR HPA; ENSG00000204842; Low tissue specificity. DR MalaCards; ATXN2; -. DR MIM; 183090; phenotype. DR MIM; 601517; gene. DR OpenTargets; ENSG00000204842; -. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 98756; Spinocerebellar ataxia type 2. DR VEuPathDB; HostDB:ENSG00000204842; -. DR eggNOG; KOG2375; Eukaryota. DR GeneTree; ENSGT00940000156812; -. DR InParanoid; Q99700; -. DR OMA; RMQMSAS; -. DR OrthoDB; 2275718at2759; -. DR PAN-GO; Q99700; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q99700; -. DR PathwayCommons; Q99700; -. DR SignaLink; Q99700; -. DR SIGNOR; Q99700; -. DR Agora; ENSG00000204842; -. DR BioGRID-ORCS; 6311; 15 hits in 1159 CRISPR screens. DR CD-CODE; 232F8A39; P-body. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; E1879998; Synthetic Condensate 000375. DR ChiTaRS; ATXN2; human. DR GeneWiki; ATXN2; -. DR GenomeRNAi; 6311; -. DR Pharos; Q99700; Tbio. DR PRO; PR:Q99700; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; Q99700; protein. DR Bgee; ENSG00000204842; Expressed in buccal mucosa cell and 197 other cell types or tissues. DR ExpressionAtlas; Q99700; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0010494; C:cytoplasmic stress granule; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:1990904; C:ribonucleoprotein complex; IDA:UniProtKB. DR GO; GO:0005802; C:trans-Golgi network; IDA:UniProtKB. DR GO; GO:0005154; F:epidermal growth factor receptor binding; IPI:UniProtKB. DR GO; GO:0003729; F:mRNA binding; IBA:GO_Central. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0002091; P:negative regulation of receptor internalization; IMP:UniProtKB. DR GO; GO:0033962; P:P-body assembly; IMP:UniProtKB. DR GO; GO:0006417; P:regulation of translation; NAS:UniProtKB. DR GO; GO:0016070; P:RNA metabolic process; NAS:UniProtKB. DR GO; GO:0050658; P:RNA transport; NAS:UniProtKB. DR GO; GO:0034063; P:stress granule assembly; IMP:UniProtKB. DR CDD; cd00600; Sm_like; 1. DR IDEAL; IID00580; -. DR InterPro; IPR045117; ATXN2-like. DR InterPro; IPR010920; LSM_dom_sf. DR InterPro; IPR009604; LsmAD_domain. DR InterPro; IPR009818; PAM2_motif. DR InterPro; IPR047575; Sm. DR InterPro; IPR025852; SM_dom_ATX. DR PANTHER; PTHR12854; ATAXIN 2-RELATED; 1. DR PANTHER; PTHR12854:SF11; ATAXIN-2; 1. DR Pfam; PF06741; LsmAD; 1. DR Pfam; PF07145; PAM2; 1. DR Pfam; PF14438; SM-ATX; 1. DR SMART; SM01272; LsmAD; 1. DR SUPFAM; SSF81995; beta-sandwich domain of Sec23/24; 1. DR SUPFAM; SSF50182; Sm-like ribonucleoproteins; 1. DR PROSITE; PS52002; SM; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Amyotrophic lateral sclerosis; KW Cytoplasm; Isopeptide bond; Methylation; Neurodegeneration; Parkinsonism; KW Phosphoprotein; Proteomics identification; Reference proteome; KW Spinocerebellar ataxia; Triplet repeat expansion; Ubl conjugation. FT CHAIN 1..1313 FT /note="Ataxin-2" FT /id="PRO_0000064756" FT DOMAIN 267..344 FT /note="Sm" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01346" FT REGION 1..255 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 459..954 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1137..1219 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1..12 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 48..65 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 104..114 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 141..154 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 166..187 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 204..234 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 235..244 FT /note="Gly residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 459..471 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 478..492 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 508..544 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 552..562 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 563..581 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 582..598 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 627..637 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 666..681 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 693..703 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 768..777 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 788..804 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 807..820 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 821..844 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 847..871 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 880..891 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 893..910 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 925..936 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1155..1192 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1206..1219 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 248 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O70305" FT MOD_RES 393 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 466 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 478 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 508 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 554 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 624 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 640 FT /note="Asymmetric dimethylarginine; alternate" FT /evidence="ECO:0000250|UniProtKB:O70305" FT MOD_RES 640 FT /note="Omega-N-methylarginine; alternate" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 642 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 684 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 728 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 741 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 772 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 784 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18220336, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 856 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O70305" FT MOD_RES 857 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 861 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:21406692" FT MOD_RES 865 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21406692" FT MOD_RES 867 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O70305" FT MOD_RES 888 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 889 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT CROSSLNK 893 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT VAR_SEQ 1..981 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011574" FT VAR_SEQ 1..265 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_057285" FT VAR_SEQ 277..300 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_057286" FT VAR_SEQ 980..995 FT /note="PLYPIPMTPMPVNQAK -> YQICPNSGKTSIIRVP (in isoform 2)" FT /evidence="ECO:0000303|PubMed:8896557" FT /id="VSP_011575" FT VAR_SEQ 982..998 FT /note="YPIPMTPMPVNQAKTYR -> MYYAVEILFNRQSAFFS (in isoform FT 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011576" FT VAR_SEQ 996..1313 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:8896557" FT /id="VSP_011577" FT VAR_SEQ 1106..1124 FT /note="ACPKLPYNKETSPSFYFAI -> V (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_057287" FT VAR_SEQ 1106..1123 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011578" FT VAR_SEQ 1124 FT /note="I -> V (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011579" FT VAR_SEQ 1244..1313 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_011582" FT VAR_SEQ 1249..1257 FT /note="AHVQSGMVP -> VIPALANFL (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011580" FT VAR_SEQ 1258..1313 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011581" FT VARIANT 107 FT /note="L -> V (in dbSNP:rs695871)" FT /evidence="ECO:0000269|PubMed:8896555, FT ECO:0000269|PubMed:8896557" FT /id="VAR_047629" FT VARIANT 248 FT /note="S -> N (in dbSNP:rs7969300)" FT /id="VAR_047630" FT CONFLICT 188 FT /note="Missing (in Ref. 1; AAB19200 and 6; CAA69589)" FT /evidence="ECO:0000305" SQ SEQUENCE 1313 AA; 140283 MW; 40A2883FF9D5D118 CRC64; MRSAAAAPRS PAVATESRRF AAARWPGWRS LQRPARRSGR GGGGAAPGPY PSAAPPPPGP GPPPSRQSSP PSASDCFGSN GNGGGAFRPG SRRLLGLGGP PRPFVVLLLP LASPGAPPAA PTRASPLGAR ASPPRSGVSL ARPAPGCPRP ACEPVYGPLT MSLKPQQQQQ QQQQQQQQQQ QQQQQQQQPP PAAANVRKPG GSGLLASPAA APSPSSSSVS SSSATAPSSV VAATSGGGRP GLGRGRNSNK GLPQSTISFD GIYANMRMVH ILTSVVGSKC EVQVKNGGIY EGVFKTYSPK CDLVLDAAHE KSTESSSGPK REEIMESILF KCSDFVVVQF KDMDSSYAKR DAFTDSAISA KVNGEHKEKD LEPWDAGELT ANEELEALEN DVSNGWDPND MFRYNEENYG VVSTYDSSLS SYTVPLERDN SEEFLKREAR ANQLAEEIES SAQYKARVAL ENDDRSEEEK YTAVQRNSSE REGHSINTRE NKYIPPGQRN REVISWGSGR QNSPRMGQPG SGSMPSRSTS HTSDFNPNSG SDQRVVNGGV PWPSPCPSPS SRPPSRYQSG PNSLPPRAAT PTRPPSRPPS RPSRPPSHPS AHGSPAPVST MPKRMSSEGP PRMSPKAQRH PRNHRVSAGR GSISSGLEFV SHNPPSEAAT PPVARTSPSG GTWSSVVSGV PRLSPKTHRP RSPRQNSIGN TPSGPVLASP QAGIIPTEAV AMPIPAASPT PASPASNRAV TPSSEAKDSR LQDQRQNSPA GNKENIKPNE TSPSFSKAEN KGISPVVSEH RKQIDDLKKF KNDFRLQPSS TSESMDQLLN KNREGEKSRD LIKDKIEPSA KDSFIENSSS NCTSGSSKPN SPSISPSILS NTEHKRGPEV TSQGVQTSSP ACKQEKDDKE EKKDAAEQVR KSTLNPNAKE FNPRSFSQPK PSTTPTSPRP QAQPSPSMVG HQQPTPVYTQ PVCFAPNMMY PVPVSPGVQP LYPIPMTPMP VNQAKTYRAV PNMPQQRQDQ HHQSAMMHPA SAAGPPIAAT PPAYSTQYVA YSPQQFPNQP LVQHVPHYQS QHPHVYSPVI QGNARMMAPP THAQPGLVSS SATQYGAHEQ THAMYACPKL PYNKETSPSF YFAISTGSLA QQYAHPNATL HPHTPHPQPS ATPTGQQQSQ HGGSHPAPSP VQHHQHQAAQ ALHLASPQQQ SAIYHAGLAP TPPSMTPASN TQSPQNSFPA AQQTVFTIHP SHVQPAYTNP PHMAHVPQAH VQSGMVPSHP TAHAPMMLMT TQPPGGPQAA LAQSALQPIP VSTTAHFPYM THPSVQAHHQ QQL // ID CNR1_HUMAN Reviewed; 472 AA. AC P21554; B2R9T4; E1P512; Q13949; Q495Z0; Q4PLI4; Q4VBM6; Q5JVL5; Q5UB37; AC Q9UNN0; DT 01-MAY-1991, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1991, sequence version 1. DT 28-JAN-2026, entry version 234. DE RecName: Full=Cannabinoid receptor 1; DE Short=CB-R; DE Short=CB1; DE AltName: Full=CANN6; GN Name=CNR1; Synonyms=CNR; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Brain stem; RX PubMed=2263478; DOI=10.1093/nar/18.23.7142; RA Gerard C., Mollereau C., Vassart G., Parmentier M.; RT "Nucleotide sequence of a human cannabinoid receptor cDNA."; RL Nucleic Acids Res. 18:7142-7142(1990). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION. RC TISSUE=Brain stem; RX PubMed=1718258; DOI=10.1042/bj2790129; RA Gerard C., Mollereau C., Vassart G., Parmentier M.; RT "Molecular cloning of a human cannabinoid receptor which is also expressed RT in testis."; RL Biochem. J. 279:129-134(1991). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Lung; RX PubMed=7876112; DOI=10.1074/jbc.270.8.3726; RA Shire D., Carillon C., Kaghad M., Calandra B., Rinaldi-Carmona M., RA Le Fur G., Caput D., Ferrara P.; RT "An amino-terminal variant of the central cannabinoid receptor resulting RT from alternative splicing."; RL J. Biol. Chem. 270:3726-3731(1995). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), FUNCTION (ISOFORMS 1; 2 AND 3), AND RP TISSUE SPECIFICITY. RC TISSUE=Fetal brain; RX PubMed=15620723; DOI=10.1016/j.febslet.2004.11.085; RA Ryberg E., Vu H.K., Larsson N., Groblewski T., Hjorth S., Elebring T., RA Sjoegren S., Greasley P.J.; RT "Identification and characterisation of a novel splice variant of the human RT CB1 receptor."; RL FEBS Lett. 579:259-264(2005). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Hippocampus; RA Kathmann M., Schlicker E.; RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Bonner T.I.; RL Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Brain tumor; RA Kumar S., Gupta S., Sharma G.; RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Kopatz S.A., Aronstam R.S., Sharma S.V.; RT "cDNA clones of human proteins involved in signal transduction sequenced by RT the Guthrie cDNA resource center (www.cdna.org)."; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Hippocampus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [12] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Lung; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [13] RP REVIEW ON INVOLVEMENT IN NERVOUS SYSTEM DISORDERS. RX PubMed=32549916; DOI=10.1007/s13167-020-00203-4; RA Reddy V., Grogan D., Ahluwalia M., Salles E.L., Ahluwalia P., Khodadadi H., RA Alverson K., Nguyen A., Raju S.P., Gaur P., Braun M., Vale F.L., RA Costigliola V., Dhandapani K., Baban B., Vaibhav K.; RT "Targeting the endocannabinoid system: a predictive, preventive, and RT personalized medicine-directed approach to the management of brain RT pathologies."; RL EPMA J. 11:217-250(2020). RN [14] RP INVOLVEMENT IN HUNTINGTON DISEASE. RX PubMed=8255419; DOI=10.1016/0306-4522(93)90352-g; RA Glass M., Faull R.L., Dragunow M.; RT "Loss of cannabinoid receptors in the substantia nigra in Huntington's RT disease."; RL Neuroscience 56:523-527(1993). RN [15] RP INVOLVEMENT IN HUNTINGTON DISEASE. RX PubMed=10828533; DOI=10.1016/s0306-4522(00)00008-7; RA Glass M., Dragunow M., Faull R.L.; RT "The pattern of neurodegeneration in Huntington's disease: a comparative RT study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations RT in the human basal ganglia in Huntington's disease."; RL Neuroscience 97:505-519(2000). RN [16] RP FUNCTION, AND INTERACTION WITH CNRIP1. RC TISSUE=Brain; RX PubMed=17895407; DOI=10.1124/mol.107.039263; RA Niehaus J.L., Liu Y., Wallis K.T., Egertova M., Bhartur S.G., RA Mukhopadhyay S., Shi S., He H., Selley D.E., Howlett A.C., Elphick M.R., RA Lewis D.L.; RT "CB1 cannabinoid receptor activity is modulated by the cannabinoid receptor RT interacting protein CRIP 1a."; RL Mol. Pharmacol. 72:1557-1566(2007). RN [17] RP ACTIVITY REGULATION. RX PubMed=18077343; DOI=10.1073/pnas.0706980105; RA Heimann A.S., Gomes I., Dale C.S., Pagano R.L., Gupta A., de Souza L.L., RA Luchessi A.D., Castro L.M., Giorgi R., Rioli V., Ferro E.S., Devi L.A.; RT "Hemopressin is an inverse agonist of CB1 cannabinoid receptors."; RL Proc. Natl. Acad. Sci. U.S.A. 104:20588-20593(2007). RN [18] RP FUNCTION, SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-415, AND MUTAGENESIS RP OF CYS-415. RX PubMed=21895628; DOI=10.1111/j.1476-5381.2011.01658.x; RA Oddi S., Dainese E., Sandiford S., Fezza F., Lanuti M., Chiurchiu V., RA Totaro A., Catanzaro G., Barcaroli D., De Laurenzi V., Centonze D., RA Mukhopadhyay S., Selent J., Howlett A.C., Maccarrone M.; RT "Effects of palmitoylation of Cys(415) in helix 8 of the CB(1) cannabinoid RT receptor on membrane localization and signalling."; RL Br. J. Pharmacol. 165:2635-2651(2012). RN [19] RP INVOLVEMENT IN OBESITY. RX PubMed=18177726; DOI=10.1016/j.cmet.2007.11.012; RA Addy C., Wright H., Van Laere K., Gantz I., Erondu N., Musser B.J., Lu K., RA Yuan J., Sanabria-Bohorquez S.M., Stoch A., Stevens C., Fong T.M., RA De Lepeleire I., Cilissen C., Cote J., Rosko K., Gendrano I.N. III, RA Nguyen A.M., Gumbiner B., Rothenberg P., de Hoon J., Bormans G., Depre M., RA Eng W.S., Ravussin E., Klein S., Blundell J., Herman G.A., Burns H.D., RA Hargreaves R.J., Wagner J., Gottesdiener K., Amatruda J.M., RA Heymsfield S.B.; RT "The acyclic CB1R inverse agonist taranabant mediates weight loss by RT increasing energy expenditure and decreasing caloric intake."; RL Cell Metab. 7:68-78(2008). RN [20] RP INVOLVEMENT IN HUNTINGTON DISEASE. RX PubMed=19524019; DOI=10.1016/j.neuroscience.2009.06.014; RA Dowie M.J., Bradshaw H.B., Howard M.L., Nicholson L.F., Faull R.L., RA Hannan A.J., Glass M.; RT "Altered CB1 receptor and endocannabinoid levels precede motor symptom RT onset in a transgenic mouse model of Huntington's disease."; RL Neuroscience 163:456-465(2009). RN [21] RP FUNCTION, AND INDUCTION BY ENDOCANNABINOID ANANDAMIDE. RX PubMed=23955712; DOI=10.1038/nm.3265; RA Jourdan T., Godlewski G., Cinar R., Bertola A., Szanda G., Liu J., Tam J., RA Han T., Mukhopadhyay B., Skarulis M.C., Ju C., Aouadi M., Czech M.P., RA Kunos G.; RT "Activation of the Nlrp3 inflammasome in infiltrating macrophages by RT endocannabinoids mediates beta cell loss in type 2 diabetes."; RL Nat. Med. 19:1132-1140(2013). RN [22] RP INVOLVEMENT IN ALZHEIMER DISEASE. RX PubMed=30096288; DOI=10.1016/j.bcp.2018.08.007; RA Aso E., Andres-Benito P., Ferrer I.; RT "Genetic deletion of CB1 cannabinoid receptors exacerbates the Alzheimer- RT like symptoms in a transgenic animal model."; RL Biochem. Pharmacol. 157:210-216(2018). RN [23] RP INVOLVEMENT IN PARKINSON DISEASE. RX PubMed=31342135; DOI=10.1007/s00259-019-04445-x; RA Ceccarini J., Casteels C., Ahmad R., Crabbe M., Van de Vliet L., RA Vanhaute H., Vandenbulcke M., Vandenberghe W., Van Laere K.; RT "Regional changes in the type 1 cannabinoid receptor are associated with RT cognitive dysfunction in Parkinson's disease."; RL Eur. J. Nucl. Med. Mol. Imaging 46:2348-2357(2019). RN [24] RP STRUCTURE BY NMR OF 338-346, INTERACTION WITH GNAI1, AND MUTAGENESIS OF RP 341-LEU-ALA-342. RX PubMed=12237474; DOI=10.1110/ps.0218402; RA Ulfers A.L., McMurry J.L., Miller A., Wang L., Kendall D.A., Mierke D.F.; RT "Cannabinoid receptor-G protein interactions: G(alphai1)-bound structures RT of IC3 and a mutant with altered G protein specificity."; RL Protein Sci. 11:2526-2531(2002). RN [25] {ECO:0007744|PDB:5TGZ} RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 99-306 AND 332-414, FUNCTION, AND RP TOPOLOGY. RX PubMed=27768894; DOI=10.1016/j.cell.2016.10.004; RA Hua T., Vemuri K., Pu M., Qu L., Han G.W., Wu Y., Zhao S., Shui W., Li S., RA Korde A., Laprairie R.B., Stahl E.L., Ho J.H., Zvonok N., Zhou H., RA Kufareva I., Wu B., Zhao Q., Hanson M.A., Bohn L.M., Makriyannis A., RA Stevens R.C., Liu Z.J.; RT "Crystal structure of the human cannabinoid receptor CB1."; RL Cell 167:750-762(2016). RN [26] {ECO:0007744|PDB:5U09} RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 90-301 AND 334-421 IN COMPLEX RP WITH INVERSE AGONIST TARANABANT, MUTAGENESIS OF THR-210, TOPOLOGY, AND RP FUNCTION. RX PubMed=27851727; DOI=10.1038/nature20613; RA Shao Z., Yin J., Chapman K., Grzemska M., Clark L., Wang J., RA Rosenbaum D.M.; RT "High-resolution crystal structure of the human CB1 cannabinoid receptor."; RL Nature 540:602-606(2016). RN [27] {ECO:0007744|PDB:7FEE, ECO:0007744|PDB:7WV9} RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 74-305 AND 333-414, INTERACTION RP WITH GNAI2, FUNCTION, AND MUTAGENESIS OF PHE-155. RX PubMed=35637350; DOI=10.1038/s41589-022-01038-y; RA Yang X., Wang X., Xu Z., Wu C., Zhou Y., Wang Y., Lin G., Li K., Wu M., RA Xia A., Liu J., Cheng L., Zou J., Yan W., Shao Z., Yang S.; RT "Molecular mechanism of allosteric modulation for the cannabinoid receptor RT CB1."; RL Nat. Chem. Biol. 18:831-840(2022). CC -!- FUNCTION: G-protein coupled receptor for endogenous cannabinoids CC (eCBs), including N-arachidonoylethanolamide (also called anandamide or CC AEA) and 2-arachidonoylglycerol (2-AG), as well as phytocannabinoids, CC such as delta(9)-tetrahydrocannabinol (THC) (PubMed:15620723, CC PubMed:27768894, PubMed:27851727, PubMed:35637350). Mediates many CC cannabinoid-induced effects, acting, among others, on food intake, CC memory loss, gastrointestinal motility, catalepsy, ambulatory activity, CC anxiety, chronic pain. Signaling typically involves reduction in cyclic CC AMP (PubMed:1718258, PubMed:21895628, PubMed:27768894). In the CC hypothalamus, may have a dual effect on mitochondrial respiration CC depending upon the agonist dose and possibly upon the cell type. CC Increases respiration at low doses, while decreases respiration at high CC doses. At high doses, CNR1 signal transduction involves G-protein CC alpha-i protein activation and subsequent inhibition of mitochondrial CC soluble adenylate cyclase, decrease in cyclic AMP concentration, CC inhibition of protein kinase A (PKA)-dependent phosphorylation of CC specific subunits of the mitochondrial electron transport system, CC including NDUFS2. In the hypothalamus, inhibits leptin-induced reactive CC oxygen species (ROS) formation and mediates cannabinoid-induced CC increase in SREBF1 and FASN gene expression. In response to CC cannabinoids, drives the release of orexigenic beta-endorphin, but not CC that of melanocyte-stimulating hormone alpha/alpha-MSH, from CC hypothalamic POMC neurons, hence promoting food intake. In the CC hippocampus, regulates cellular respiration and energy production in CC response to cannabinoids. Involved in cannabinoid-dependent CC depolarization-induced suppression of inhibition (DSI), a process in CC which depolarization of CA1 postsynaptic pyramidal neurons mobilizes CC eCBs, which retrogradely activate presynaptic CB1 receptors, CC transiently decreasing GABAergic inhibitory neurotransmission. Also CC reduces excitatory synaptic transmission (By similarity). In superior CC cervical ganglions and cerebral vascular smooth muscle cells, inhibits CC voltage-gated Ca(2+) channels in a constitutive, as well as agonist- CC dependent manner (PubMed:17895407). In cerebral vascular smooth muscle CC cells, cannabinoid-induced inhibition of voltage-gated Ca(2+) channels CC leads to vasodilation and decreased vascular tone (By similarity). CC Induces leptin production in adipocytes and reduces LRP2-mediated CC leptin clearance in the kidney, hence participating in hyperleptinemia. CC In adipose tissue, CNR1 signaling leads to increased expression of CC SREBF1, ACACA and FASN genes (By similarity). In the liver, activation CC by endocannabinoids leads to increased de novo lipogenesis and reduced CC fatty acid catabolism, associated with increased expression of CC SREBF1/SREBP-1, GCK, ACACA, ACACB and FASN genes. May also affect de CC novo cholesterol synthesis and HDL-cholesteryl ether uptake. CC Peripherally modulates energy metabolism (By similarity). In high CC carbohydrate diet-induced obesity, may decrease the expression of CC mitochondrial dihydrolipoyl dehydrogenase/DLD in striated muscles, as CC well as that of selected glucose/ pyruvate metabolic enzymes, hence CC affecting energy expenditure through mitochondrial metabolism (By CC similarity). In response to cannabinoid anandamide, elicits a pro- CC inflammatory response in macrophages, which involves NLRP3 inflammasome CC activation and IL1B and IL18 secretion (By similarity). In macrophages CC infiltrating pancreatic islets, this process may participate in the CC progression of type-2 diabetes and associated loss of pancreatic beta- CC cells (PubMed:23955712). {ECO:0000250|UniProtKB:O02777, CC ECO:0000250|UniProtKB:P47746, ECO:0000269|PubMed:15620723, CC ECO:0000269|PubMed:1718258, ECO:0000269|PubMed:17895407, CC ECO:0000269|PubMed:21895628, ECO:0000269|PubMed:23955712, CC ECO:0000269|PubMed:27768894, ECO:0000269|PubMed:27851727, CC ECO:0000269|PubMed:35637350}. CC -!- FUNCTION: [Isoform 1]: Binds both 2-arachidonoylglycerol (2-AG) and CC anandamide. {ECO:0000269|PubMed:15620723}. CC -!- FUNCTION: [Isoform 2]: Only binds 2-arachidonoylglycerol (2-AG) with CC high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an CC inverse agonist on isoform 2 in assays measuring GTP binding to CC membranes. {ECO:0000269|PubMed:15620723}. CC -!- FUNCTION: [Isoform 3]: Only binds 2-arachidonoylglycerol (2-AG) with CC high affinity. Contrary to its effect on isoform 1, 2-AG behaves as an CC inverse agonist on isoform 3 in assays measuring GTP binding to CC membranes. {ECO:0000269|PubMed:15620723}. CC -!- ACTIVITY REGULATION: Hemopressin, a peptide derived from hemoglobin CC subunit alpha (HBA1 and/or HBA2), acts as an antagonist peptide: CC hemopressin-binding efficiently blocks cannabinoid receptor CNR1 and CC subsequent signaling. {ECO:0000269|PubMed:18077343}. CC -!- SUBUNIT: Interacts (via C-terminus) with CNRIP1; this interaction CC attenuates constitutive, but not agonist-dependent, inhibition of CC voltage-gated Ca(2+) channels in neurons (PubMed:17895407). Associates CC with G protein alpha subunits, including G(i) alpha-1/GNAI1, G(i) CC alpha-2/GNAI2, G(i) alpha-3/GNAI3 and G(o)-alpha/GNAO1; palmitoylation CC is important for interaction with GNAI3 and GNAO1 (PubMed:12237474). CC {ECO:0000269|PubMed:12237474, ECO:0000269|PubMed:17895407, CC ECO:0000269|PubMed:35637350}. CC -!- INTERACTION: CC P21554; P29274: ADORA2A; NbExp=8; IntAct=EBI-2909859, EBI-2902702; CC P21554; P21554: CNR1; NbExp=8; IntAct=EBI-2909859, EBI-2909859; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:21895628}; CC Multi-pass membrane protein {ECO:0000269|PubMed:27768894, CC ECO:0000269|PubMed:27851727}. Membrane raft CC {ECO:0000269|PubMed:21895628}. Mitochondrion outer membrane CC {ECO:0000250|UniProtKB:P47746}. Cell projection, axon CC {ECO:0000250|UniProtKB:P20272}. Presynapse CC {ECO:0000250|UniProtKB:P20272}. Note=Unexpectedly, in the mitochondria, CC the C-terminus is located in the mitochondrial intermembrane space, a CC compartment topologically considered as extracellular. In canonical CC seven-transmembrane G-protein coupled receptors, the C-terminus is CC cytosolic (By similarity). Found on presynaptic axon terminals in some CC GABAergic neurons in the somatosensory cortex (By similarity). CC {ECO:0000250|UniProtKB:P20272, ECO:0000250|UniProtKB:P47746}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; Synonyms=Long; CC IsoId=P21554-1; Sequence=Displayed; CC Name=2; Synonyms=CB1a {ECO:0000303|PubMed:15620723}, Short; CC IsoId=P21554-2; Sequence=VSP_001868; CC Name=3; Synonyms=CB1b {ECO:0000303|PubMed:15620723}; CC IsoId=P21554-3; Sequence=VSP_016529; CC -!- TISSUE SPECIFICITY: Widely expressed, with highest levels in fetal and CC adult brain. Expression levels of isoform 2 and isoform 3 are much CC lower than those of isoform 1. {ECO:0000269|PubMed:15620723}. CC -!- INDUCTION: Up-regulated by endocannabinoid anandamide. CC {ECO:0000269|PubMed:23955712}. CC -!- PTM: Palmitoylation at Cys-415 is important for recruitment at plasma CC membrane and lipid rafts and association with G protein alpha subunits. CC {ECO:0000269|PubMed:21895628}. CC -!- DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized by CC an increase of body weight beyond the limitation of skeletal and CC physical requirements, as the result of excessive accumulation of body CC fat. {ECO:0000269|PubMed:18177726}. Note=The protein represented in CC this entry may be involved in disease pathogenesis. May contribute to CC the development of diet-induced obesity and several obesity-associated CC features, such as dyslipidemia and liver steatosis, regulating CC peripheral lipogenesis, energy expenditure and feeding behavior. CNR1 CC inverse agonists have been shown to reduce body weight and improve CC metabolic abnormalities in obese subjects, although adverse CC neuropsychiatric effects, including anxiety, irritability, and CC depressed mood, halted their therapeutic development (PubMed:18177726). CC In obese mice, peripherally restricted CNR1 inverse agonists have been CC shown to normalize metabolic abnormalities, including insulin CC resistance and fatty liver, and to reverse leptin resistance. CC {ECO:0000269|PubMed:18177726}. CC -!- DISEASE: Note=Dysfunction of the endogenous cannabinoid system CC including CNR1 has been implicated in the pathogenesis of a number of CC central nervous system disorders, including Huntington disease, CC Parkinson disease, and Alzheimer disease (PubMed:32549916). In post- CC mortem brains from Huntington disease patients, a progressive CNR1 loss CC has been observed in the caudate nucleus, putamen, and substantia nigra CC pars reticulata, and altered expression and abnormal endocannabinoid CC levels precede motor symptoms in a disease mouse model CC (PubMed:10828533, PubMed:19524019, PubMed:8255419). In Parkinson CC disease, low CNR1 expression in mid-superior frontal gyrus and mid- CC cingulate cortex has been associated with poor mind, poor executive CC functioning and poor episode memory, while patients with more severe CC visuospatial dysfunction showed decreased receptor availability in the CC precuneus, mid-cingulate, supplementary motor cortex, inferior CC orbitofrontal gyrus and thalamus (PubMed:31342135). In an animal model CC for Alzheimer disease, CNR1 heterozygous deletion has been associated CC with decreased levels of postsynaptic density protein 95 (DLG4/PSD95) CC and accelerated memory impairment, suggesting synaptic dysfunction and CC a crucial role for CNR1 in the progression of disease symptoms CC (PubMed:10828533, PubMed:19524019, PubMed:30096288, PubMed:31342135, CC PubMed:8255419). {ECO:0000269|PubMed:10828533, CC ECO:0000269|PubMed:19524019, ECO:0000269|PubMed:30096288, CC ECO:0000269|PubMed:31342135, ECO:0000269|PubMed:32549916, CC ECO:0000269|PubMed:8255419}. CC -!- MISCELLANEOUS: High-fat diet also increases the hepatic levels of CNR1 CC ligand anandamide, but not that of 2-arachidonoylglycerol. CC {ECO:0000250|UniProtKB:P47746}. CC -!- MISCELLANEOUS: [Isoform 2]: Dubious isoform. A putative downstream CC initiation AUG is used to produce isoform 2 (PubMed:1718258). The use CC of the first AUG (same as isoform 1) gives a truncated protein of 36 CC AA. {ECO:0000305|PubMed:1718258}. CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family. CC {ECO:0000255|PROSITE-ProRule:PRU00521}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X54937; CAA38699.1; -; mRNA. DR EMBL; X81120; CAA57018.1; -; mRNA. DR EMBL; X81121; CAA57019.1; -; mRNA. DR EMBL; AY766182; AAV35030.1; -; mRNA. DR EMBL; AF107262; AAD34320.1; -; mRNA. DR EMBL; U73304; AAB18200.1; -; Genomic_DNA. DR EMBL; DQ067455; AAY68486.1; -; mRNA. DR EMBL; AY225225; AAO67710.1; -; Genomic_DNA. DR EMBL; AL136096; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AK313908; BAG36631.1; -; mRNA. DR EMBL; CH471051; EAW48574.1; -; Genomic_DNA. DR EMBL; CH471051; EAW48575.1; -; Genomic_DNA. DR EMBL; CH471051; EAW48576.1; -; Genomic_DNA. DR EMBL; BC074811; AAH74811.1; -; mRNA. DR EMBL; BC074812; AAH74812.1; -; mRNA. DR EMBL; BC095513; AAH95513.1; -; mRNA. DR EMBL; BC100968; AAI00969.1; -; mRNA. DR EMBL; BC100969; AAI00970.1; -; mRNA. DR EMBL; BC100970; AAI00971.1; -; mRNA. DR EMBL; BC100971; AAI00972.1; -; mRNA. DR CCDS; CCDS5015.1; -. [P21554-1] DR CCDS; CCDS5016.2; -. [P21554-3] DR PIR; S17595; S17595. DR RefSeq; NP_001153698.1; NM_001160226.3. [P21554-1] DR RefSeq; NP_001153730.1; NM_001160258.3. [P21554-1] DR RefSeq; NP_001153731.1; NM_001160259.3. [P21554-1] DR RefSeq; NP_001352798.1; NM_001365869.2. [P21554-1] DR RefSeq; NP_001352799.1; NM_001365870.2. [P21554-1] DR RefSeq; NP_001352801.1; NM_001365872.2. [P21554-1] DR RefSeq; NP_001352803.1; NM_001365874.3. [P21554-1] DR RefSeq; NP_001357474.1; NM_001370545.1. [P21554-1] DR RefSeq; NP_001357475.1; NM_001370546.1. [P21554-1] DR RefSeq; NP_001357476.1; NM_001370547.1. [P21554-1] DR RefSeq; NP_001411023.1; NM_001424094.1. [P21554-1] DR RefSeq; NP_001411024.1; NM_001424095.1. [P21554-1] DR RefSeq; NP_001411025.1; NM_001424096.1. [P21554-1] DR RefSeq; NP_001411026.1; NM_001424097.1. [P21554-1] DR RefSeq; NP_001411027.1; NM_001424098.1. [P21554-1] DR RefSeq; NP_057167.2; NM_016083.4. [P21554-1] DR RefSeq; NP_149421.2; NM_033181.4. [P21554-3] DR RefSeq; XP_047274127.1; XM_047418171.1. [P21554-1] DR RefSeq; XP_047274128.1; XM_047418172.1. [P21554-1] DR RefSeq; XP_047274129.1; XM_047418173.1. [P21554-1] DR RefSeq; XP_054210179.1; XM_054354204.1. [P21554-1] DR RefSeq; XP_054210180.1; XM_054354205.1. [P21554-1] DR RefSeq; XP_054210181.1; XM_054354206.1. [P21554-1] DR PDB; 1LVQ; NMR; -; A=338-346. DR PDB; 1LVR; NMR; -; A=338-346. DR PDB; 2B0Y; NMR; -; A=400-414. DR PDB; 2KOE; NMR; -; A=377-414. DR PDB; 2MZ2; NMR; -; A=400-414. DR PDB; 2MZ3; NMR; -; A=400-414. DR PDB; 2MZA; NMR; -; A=400-414. DR PDB; 5TGZ; X-ray; 2.80 A; A=99-306, A=332-414. DR PDB; 5U09; X-ray; 2.60 A; A=90-301, A=333-421. DR PDB; 5XR8; X-ray; 2.95 A; A=99-306, A=332-414. DR PDB; 5XRA; X-ray; 2.80 A; A=99-306, A=332-414. DR PDB; 6KPG; EM; 3.00 A; R=71-425. DR PDB; 6KQI; X-ray; 3.25 A; A=94-301, A=334-413. DR PDB; 6N4B; EM; 3.00 A; R=1-472. DR PDB; 7FEE; X-ray; 2.70 A; A=74-305, A=333-414. DR PDB; 7V3Z; X-ray; 3.29 A; A=102-306, A=336-414. DR PDB; 7WV9; EM; 3.36 A; R=1-472. DR PDB; 8GAG; EM; 3.30 A; R=1-472. DR PDB; 8GHV; EM; 2.80 A; D=1-472. DR PDB; 8IKG; EM; 3.40 A; R=99-408. DR PDB; 8IKH; EM; 3.30 A; R=99-408. DR PDB; 8K8J; EM; 2.88 A; R=71-425. DR PDB; 8WRZ; EM; 3.60 A; R=71-432. DR PDB; 8WU1; EM; 3.20 A; R=1-413. DR PDB; 9B54; EM; 2.86 A; R=1-472. DR PDB; 9B65; EM; 3.03 A; R=1-472. DR PDB; 9B9Y; EM; 3.50 A; R=96-301, R=334-416. DR PDB; 9B9Z; EM; 3.30 A; R=96-301, R=334-416. DR PDB; 9BA0; EM; 3.13 A; R=96-301, R=334-416. DR PDB; 9DGI; EM; 3.35 A; R=1-472. DR PDB; 9EGO; EM; 3.20 A; R=1-472. DR PDB; 9ERX; EM; 2.90 A; R=2-472. DR PDBsum; 1LVQ; -. DR PDBsum; 1LVR; -. DR PDBsum; 2B0Y; -. DR PDBsum; 2KOE; -. DR PDBsum; 2MZ2; -. DR PDBsum; 2MZ3; -. DR PDBsum; 2MZA; -. DR PDBsum; 5TGZ; -. DR PDBsum; 5U09; -. DR PDBsum; 5XR8; -. DR PDBsum; 5XRA; -. DR PDBsum; 6KPG; -. DR PDBsum; 6KQI; -. DR PDBsum; 6N4B; -. DR PDBsum; 7FEE; -. DR PDBsum; 7V3Z; -. DR PDBsum; 7WV9; -. DR PDBsum; 8GAG; -. DR PDBsum; 8GHV; -. DR PDBsum; 8IKG; -. DR PDBsum; 8IKH; -. DR PDBsum; 8K8J; -. DR PDBsum; 8WRZ; -. DR PDBsum; 8WU1; -. DR PDBsum; 9B54; -. DR PDBsum; 9B65; -. DR PDBsum; 9B9Y; -. DR PDBsum; 9B9Z; -. DR PDBsum; 9BA0; -. DR PDBsum; 9DGI; -. DR PDBsum; 9EGO; -. DR PDBsum; 9ERX; -. DR AlphaFoldDB; P21554; -. DR EMDB; EMD-0339; -. DR EMDB; EMD-0745; -. DR EMDB; EMD-19929; -. DR EMDB; EMD-29898; -. DR EMDB; EMD-32850; -. DR EMDB; EMD-35511; -. DR EMDB; EMD-35512; -. DR EMDB; EMD-36951; -. DR EMDB; EMD-37795; -. DR EMDB; EMD-40052; -. DR EMDB; EMD-44199; -. DR EMDB; EMD-44247; -. DR EMDB; EMD-44392; -. DR EMDB; EMD-44393; -. DR EMDB; EMD-44394; -. DR EMDB; EMD-46828; -. DR EMDB; EMD-47992; -. DR SMR; P21554; -. DR BioGRID; 107668; 11. DR CORUM; P21554; -. DR DIP; DIP-61575N; -. DR FunCoup; P21554; 1275. DR IntAct; P21554; 12. DR STRING; 9606.ENSP00000358513; -. DR BindingDB; P21554; -. DR ChEMBL; CHEMBL218; -. DR DrugBank; DB09061; Cannabidiol. DR DrugBank; DB14737; Cannabinol. DR DrugBank; DB05750; Drinabant. DR DrugBank; DB00470; Dronabinol. DR DrugBank; DB14009; Medical Cannabis. DR DrugBank; DB00486; Nabilone. DR DrugBank; DB14011; Nabiximols. DR DrugBank; DB16495; Oleic monoethanolamide. DR DrugBank; DB01083; Orlistat. DR DrugBank; DB11745; Otenabant. DR DrugBank; DB13495; Paraoxon. DR DrugBank; DB09288; Propacetamol. DR DrugBank; DB02955; Ricinoleic acid. DR DrugBank; DB06155; Rimonabant. DR DrugBank; DB05077; SLV319. DR DrugBank; DB13070; Surinabant. DR DrugBank; DB06624; Taranabant. DR DrugBank; DB11755; Tetrahydrocannabivarin. DR DrugBank; DB05201; V24343. DR DrugBank; DB13950; WIN 55212-2. DR DrugCentral; P21554; -. DR GuidetoPHARMACOLOGY; 56; -. DR SwissLipids; SLP:000001607; -. DR TCDB; 9.A.14.2.2; the g-protein-coupled receptor (gpcr) family. DR GlyCosmos; P21554; 2 sites, No reported glycans. DR GlyGen; P21554; 2 sites. DR iPTMnet; P21554; -. DR PhosphoSitePlus; P21554; -. DR SwissPalm; P21554; -. DR BioMuta; CNR1; -. DR DMDM; 115562; -. DR MassIVE; P21554; -. DR PaxDb; 9606-ENSP00000358513; -. DR PeptideAtlas; P21554; -. DR ProteomicsDB; 53875; -. [P21554-1] DR ProteomicsDB; 53876; -. [P21554-2] DR ProteomicsDB; 53877; -. [P21554-3] DR ABCD; P21554; 62 sequenced antibodies. DR Antibodypedia; 3355; 718 antibodies from 42 providers. DR DNASU; 1268; -. DR Ensembl; ENST00000369499.3; ENSP00000358511.2; ENSG00000118432.14. [P21554-1] DR Ensembl; ENST00000369501.3; ENSP00000358513.2; ENSG00000118432.14. [P21554-1] DR Ensembl; ENST00000428600.3; ENSP00000412192.2; ENSG00000118432.14. [P21554-1] DR Ensembl; ENST00000468898.2; ENSP00000420188.1; ENSG00000118432.14. [P21554-3] DR Ensembl; ENST00000549890.2; ENSP00000446819.1; ENSG00000118432.14. [P21554-1] DR Ensembl; ENST00000551417.2; ENSP00000446702.2; ENSG00000118432.14. [P21554-1] DR GeneID; 1268; -. DR KEGG; hsa:1268; -. DR MANE-Select; ENST00000369501.3; ENSP00000358513.2; NM_016083.6; NP_057167.2. DR AGR; HGNC:2159; -. DR ClinPGx; PA26681; -. DR CTD; 1268; -. DR DisGeNET; 1268; -. DR GeneCards; CNR1; -. DR HGNC; HGNC:2159; CNR1. DR HPA; ENSG00000118432; Tissue enhanced (adipose tissue, pituitary gland). DR MIM; 114610; gene. DR MIM; 601665; phenotype. DR OpenTargets; ENSG00000118432; -. DR VEuPathDB; HostDB:ENSG00000118432; -. DR eggNOG; KOG3656; Eukaryota. DR GeneTree; ENSGT01140000282530; -. DR HOGENOM; CLU_009579_7_0_1; -. DR InParanoid; P21554; -. DR OMA; HKHANSA; -. DR OrthoDB; 5966748at2759; -. DR PAN-GO; P21554; 6 GO annotations based on evolutionary models. DR PhylomeDB; P21554; -. DR PathwayCommons; P21554; -. DR Reactome; R-HSA-373076; Class A/1 (Rhodopsin-like receptors). DR Reactome; R-HSA-418594; G alpha (i) signalling events. DR SignaLink; P21554; -. DR SIGNOR; P21554; -. DR Agora; ENSG00000118432; -. DR BioGRID-ORCS; 1268; 19 hits in 1157 CRISPR screens. DR ChiTaRS; CNR1; human. DR EvolutionaryTrace; P21554; -. DR GeneWiki; Cannabinoid_receptor_type_1; -. DR GenomeRNAi; 1268; -. DR Pharos; P21554; Tclin. DR PRO; PR:P21554; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; P21554; protein. DR Bgee; ENSG00000118432; Expressed in ganglionic eminence and 150 other cell types or tissues. DR ExpressionAtlas; P21554; baseline and differential. DR GO; GO:0015629; C:actin cytoskeleton; IDA:HPA. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0098982; C:GABA-ergic synapse; IEA:Ensembl. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0030426; C:growth cone; IEA:Ensembl. DR GO; GO:0045121; C:membrane raft; IEA:UniProtKB-SubCell. DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0042734; C:presynaptic membrane; IEA:Ensembl. DR GO; GO:0004949; F:cannabinoid receptor activity; IDA:UniProtKB. DR GO; GO:0004930; F:G protein-coupled receptor activity; IBA:GO_Central. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IBA:GO_Central. DR GO; GO:0007188; P:adenylate cyclase-modulating G protein-coupled receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0007413; P:axonal fasciculation; IEA:Ensembl. DR GO; GO:0038171; P:cannabinoid signaling pathway; IDA:UniProtKB. DR GO; GO:0007187; P:G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; TAS:ProtInc. DR GO; GO:0042593; P:glucose homeostasis; IEA:Ensembl. DR GO; GO:0099509; P:regulation of presynaptic cytosolic calcium ion concentration; IEA:Ensembl. DR GO; GO:0098921; P:retrograde trans-synaptic signaling by endocannabinoid; IEA:Ensembl. DR CDD; cd15340; 7tmA_CB1; 1. DR FunFam; 1.20.1070.10:FF:000072; Cannabinoid receptor 1; 1. DR Gene3D; 1.20.1070.10; Rhodopsin 7-helix transmembrane proteins; 1. DR InterPro; IPR000810; Canbinoid_rcpt_1. DR InterPro; IPR002230; Cnbnoid_rcpt. DR InterPro; IPR000276; GPCR_Rhodpsn. DR InterPro; IPR017452; GPCR_Rhodpsn_7TM. DR PANTHER; PTHR22750; G-PROTEIN COUPLED RECEPTOR; 1. DR Pfam; PF00001; 7tm_1; 1. DR PIRSF; PIRSF037995; Cnoid_rcpt_1; 1. DR PRINTS; PR00522; CANABINOID1R. DR PRINTS; PR00362; CANNABINOIDR. DR PRINTS; PR00237; GPCRRHODOPSN. DR SMART; SM01381; 7TM_GPCR_Srsx; 1. DR SUPFAM; SSF81321; Family A G protein-coupled receptor-like; 1. DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1. DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Cell projection; KW G-protein coupled receptor; Glycoprotein; Lipoprotein; Membrane; KW Mitochondrion; Mitochondrion outer membrane; Neurodegeneration; Obesity; KW Palmitate; Phosphoprotein; Proteomics identification; Receptor; KW Reference proteome; Synapse; Transducer; Transmembrane; KW Transmembrane helix. FT CHAIN 1..472 FT /note="Cannabinoid receptor 1" FT /id="PRO_0000069314" FT TOPO_DOM 1..116 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 117..142 FT /note="Helical; Name=1" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 143..154 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 155..175 FT /note="Helical; Name=2" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 176..187 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 188..212 FT /note="Helical; Name=3" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 213..232 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 233..255 FT /note="Helical; Name=4" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 256..273 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 274..299 FT /note="Helical; Name=5" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 300..344 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 345..365 FT /note="Helical; Name=6" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 366..377 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TRANSMEM 378..399 FT /note="Helical; Name=7" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT TOPO_DOM 400..472 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:27768894, FT ECO:0000269|PubMed:27851727" FT REGION 2..23 FT /note="Required for mitochondrial localization" FT /evidence="ECO:0000250|UniProtKB:P47746" FT MOD_RES 425 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P47746" FT MOD_RES 429 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P47746" FT LIPID 415 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:21895628" FT CARBOHYD 77 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 83 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VAR_SEQ 1..89 FT /note="MKSILDGLADTTFRTITTDLLYVGSNDIQYEDIKGDMASKLGYFPQKFPLTS FT FRGSPFQEKMTAGDNPQLVPADQVNITEFYNKSLSSF -> MALQIPPSAPSPLTSCTW FT AQMTFSTKTS (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7876112" FT /id="VSP_001868" FT VAR_SEQ 22..54 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15620723" FT /id="VSP_016529" FT MUTAGEN 155 FT /note="F->V: Enhanced G(i) signaling activation ability." FT /evidence="ECO:0000269|PubMed:35637350" FT MUTAGEN 155 FT /note="F->W: Reduced agonist-induced receptor activation." FT /evidence="ECO:0000269|PubMed:35637350" FT MUTAGEN 210 FT /note="T->A: 7-fold lower affinity for a synthetic agonist, FT CP55940, possibly due the stabilization of an inactive FT conformation." FT /evidence="ECO:0000269|PubMed:27851727" FT MUTAGEN 341..342 FT /note="LA->AL: Loss of activity, when assayed for GNAI1 FT GTPase stimulatory activity." FT /evidence="ECO:0000269|PubMed:12237474" FT MUTAGEN 415 FT /note="C->A: Loss of palmitoylation, marked loss of FT association with lipid rafts on the plasma membrane and FT loss of activity, when assayed for downstream GTP-binding FT and reduction in cAMP levels." FT /evidence="ECO:0000269|PubMed:21895628" FT CONFLICT 94 FT /note="E -> G (in Ref. 12; AAH95513)" FT /evidence="ECO:0000305" FT CONFLICT 103 FT /note="M -> I (in Ref. 12; AAH95513)" FT /evidence="ECO:0000305" FT CONFLICT 149 FT /note="C -> R (in Ref. 12; AAH95513)" FT /evidence="ECO:0000305" FT CONFLICT 200 FT /note="F -> L (in Ref. 5; AAD34320)" FT /evidence="ECO:0000305" FT CONFLICT 216 FT /note="I -> V (in Ref. 5; AAD34320)" FT /evidence="ECO:0000305" FT CONFLICT 246 FT /note="V -> A (in Ref. 5; AAD34320)" FT /evidence="ECO:0000305" FT CONFLICT 298 FT /note="L -> P (in Ref. 12; AAH95513)" FT /evidence="ECO:0000305" FT CONFLICT 332 FT /note="P -> S (in Ref. 12; AAI00972)" FT /evidence="ECO:0000305" FT STRAND 100..102 FT /evidence="ECO:0007829|PDB:7FEE" FT HELIX 105..107 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 113..143 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 145..148 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 151..153 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 154..178 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 186..219 FT /evidence="ECO:0007829|PDB:5U09" FT TURN 221..223 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 224..227 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 230..249 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 250..253 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 257..260 FT /evidence="ECO:0007829|PDB:5U09" FT STRAND 266..268 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 273..300 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 302..305 FT /evidence="ECO:0007829|PDB:6KPG" FT HELIX 306..309 FT /evidence="ECO:0007829|PDB:8K8J" FT HELIX 334..367 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 375..400 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 402..409 FT /evidence="ECO:0007829|PDB:5U09" FT HELIX 411..415 FT /evidence="ECO:0007829|PDB:2B0Y" SQ SEQUENCE 472 AA; 52858 MW; 1D2E49061D12ABF2 CRC64; MKSILDGLAD TTFRTITTDL LYVGSNDIQY EDIKGDMASK LGYFPQKFPL TSFRGSPFQE KMTAGDNPQL VPADQVNITE FYNKSLSSFK ENEENIQCGE NFMDIECFMV LNPSQQLAIA VLSLTLGTFT VLENLLVLCV ILHSRSLRCR PSYHFIGSLA VADLLGSVIF VYSFIDFHVF HRKDSRNVFL FKLGGVTASF TASVGSLFLT AIDRYISIHR PLAYKRIVTR PKAVVAFCLM WTIAIVIAVL PLLGWNCEKL QSVCSDIFPH IDETYLMFWI GVTSVLLLFI VYAYMYILWK AHSHAVRMIQ RGTQKSIIIH TSEDGKVQVT RPDQARMDIR LAKTLVLILV VLIICWGPLL AIMVYDVFGK MNKLIKTVFA FCSMLCLLNS TVNPIIYALR SKDLRHAFRS MFPSCEGTAQ PLDNSMGDSD CLHKHANNAA SVHRAAESCI KSTVKIAKVT MSVSTDTSAE AL // ID DCTN1_HUMAN Reviewed; 1278 AA. AC Q14203; A8MY36; B4DM45; E9PFS5; E9PGE1; G5E9H4; O95296; Q6IQ37; Q9BRM9; AC Q9UIU1; Q9UIU2; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 18-OCT-2001, sequence version 3. DT 28-JAN-2026, entry version 231. DE RecName: Full=Dynactin subunit 1; DE AltName: Full=150 kDa dynein-associated polypeptide; DE AltName: Full=DAP-150; DE Short=DP-150; DE AltName: Full=p135; DE AltName: Full=p150-glued; GN Name=DCTN1 {ECO:0000312|HGNC:HGNC:2711}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING. RX PubMed=9799602; DOI=10.1006/geno.1998.5542; RA Collin G.B., Nishina P.M., Marshall J.D., Naggert J.K.; RT "Human DCTN1: genomic structure and evaluation as a candidate for Alstrom RT syndrome."; RL Genomics 53:359-364(1998). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4). RC TISSUE=Brain, and Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 9-1278. RC TISSUE=Brain; RX PubMed=8838327; DOI=10.1006/geno.1996.0068; RA Holzbaur E.L.F., Tokito M.K.; RT "Localization of the DCTN1 gene encoding p150Glued to human chromosome 2p13 RT by fluorescence in situ hybridization."; RL Genomics 31:398-399(1996). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 9-1278 (ISOFORM 6), AND ALTERNATIVE SPLICING. RC TISSUE=Brain; RX PubMed=8856662; DOI=10.1091/mbc.7.8.1167; RA Tokito M.K., Howland D.S., Lee V.M.-Y., Holzbaur E.L.F.; RT "Functionally distinct isoforms of dynactin are expressed in human RT neurons."; RL Mol. Biol. Cell 7:1167-1180(1996). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 18-1278. RX PubMed=9805007; DOI=10.1016/s0167-4781(98)00195-x; RA Tokito M.K., Holzbaur E.L.F.; RT "The genomic structure of DCTN1, a candidate gene for limb-girdle muscular RT dystrophy."; RL Biochim. Biophys. Acta 1442:432-436(1998). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1081-1278. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [10] RP INTERACTION WITH MAPRE1; MAPRE2 AND MAPRE3. RX PubMed=14514668; DOI=10.1074/jbc.m306194200; RA Bu W., Su L.-K.; RT "Characterization of functional domains of human EB1 family proteins."; RL J. Biol. Chem. 278:49721-49731(2003). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY, AND SUBCELLULAR LOCATION [LARGE SCALE RP ANALYSIS]. RC TISSUE=Lymphoblast; RX PubMed=14654843; DOI=10.1038/nature02166; RA Andersen J.S., Wilkinson C.J., Mayor T., Mortensen P., Nigg E.A., Mann M.; RT "Proteomic characterization of the human centrosome by protein correlation RT profiling."; RL Nature 426:570-574(2003). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein phosphorylation RT analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [13] RP UBIQUITINATION, AND INTERACTION WITH FBXL5. RX PubMed=17532294; DOI=10.1016/j.bbrc.2007.05.068; RA Zhang N., Liu J., Ding X., Aikhionbare F., Jin C., Yao X.; RT "FBXL5 interacts with p150Glued and regulates its ubiquitination."; RL Biochem. Biophys. Res. Commun. 359:34-39(2007). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [15] RP INTERACTION WITH SNX6. RX PubMed=19935774; DOI=10.1038/cr.2009.130; RA Hong Z., Yang Y., Zhang C., Niu Y., Li K., Zhao X., Liu J.J.; RT "The retromer component SNX6 interacts with dynactin p150(Glued) and RT mediates endosome-to-TGN transport."; RL Cell Res. 19:1334-1349(2009). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-108, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [17] RP INTERACTION WITH ECPAS. RX PubMed=20682791; DOI=10.1074/jbc.m110.154120; RA Gorbea C., Pratt G., Ustrell V., Bell R., Sahasrabudhe S., Hughes R.E., RA Rechsteiner M.; RT "A protein interaction network for Ecm29 links the 26 S proteasome to RT molecular motors and endosomal components."; RL J. Biol. Chem. 285:31616-31633(2010). RN [18] RP INTERACTION WITH PARD6A, AND SUBCELLULAR LOCATION. RX PubMed=20719959; DOI=10.1091/mbc.e10-05-0430; RA Kodani A., Tonthat V., Wu B., Suetterlin C.; RT "Par6 alpha interacts with the dynactin subunit p150 Glued and is a RT critical regulator of centrosomal protein recruitment."; RL Mol. Biol. Cell 21:3376-3385(2010). RN [19] RP INTERACTION WITH DYNAP. RX PubMed=20978158; DOI=10.1158/1535-7163.mct-10-0730; RA Kunoh T., Noda T., Koseki K., Sekigawa M., Takagi M., Shin-ya K., RA Goshima N., Iemura S., Natsume T., Wada S., Mukai Y., Ohta S., Sasaki R., RA Mizukami T.; RT "A novel human dynactin-associated protein, dynAP, promotes activation of RT Akt, and ergosterol-related compounds induce dynAP-dependent apoptosis of RT human cancer cells."; RL Mol. Cancer Ther. 9:2934-2942(2010). RN [20] RP PHOSPHORYLATION AT SER-179 AND SER-212, MUTAGENESIS OF SER-179 AND SER-212, RP INTERACTION WITH PLK1 AND CLIP1, AND SUBCELLULAR LOCATION. RX PubMed=20679239; DOI=10.1073/pnas.1006615107; RA Li H., Liu X.S., Yang X., Song B., Wang Y., Liu X.; RT "Polo-like kinase 1 phosphorylation of p150Glued facilitates nuclear RT envelope breakdown during prophase."; RL Proc. Natl. Acad. Sci. U.S.A. 107:14633-14638(2010). RN [21] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [22] RP INTERACTION WITH DCDC1. RX PubMed=22159412; DOI=10.1242/jcs.085407; RA Kaplan A., Reiner O.; RT "Linking cytoplasmic dynein and transport of Rab8 vesicles to the midbody RT during cytokinesis by the doublecortin domain-containing 5 protein."; RL J. Cell Sci. 124:3989-4000(2011). RN [23] RP INTERACTION WITH CLN3. RX PubMed=22261744; DOI=10.1007/s00018-011-0913-1; RA Uusi-Rauva K., Kyttala A., van der Kant R., Vesa J., Tanhuanpaa K., RA Neefjes J., Olkkonen V.M., Jalanko A.; RT "Neuronal ceroid lipofuscinosis protein CLN3 interacts with motor proteins RT and modifies location of late endosomal compartments."; RL Cell. Mol. Life Sci. 69:2075-2089(2012). RN [24] RP INTERACTION WITH CEP131. RX PubMed=22797915; DOI=10.1242/jcs.104059; RA Staples C.J., Myers K.N., Beveridge R.D., Patil A.A., Lee A.J., Swanton C., RA Howell M., Boulton S.J., Collis S.J.; RT "The centriolar satellite protein Cep131 is important for genome RT stability."; RL J. Cell Sci. 125:4770-4779(2012). RN [25] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=22327364; DOI=10.1038/ncb2440; RA Kiyomitsu T., Cheeseman I.M.; RT "Chromosome- and spindle-pole-derived signals generate an intrinsic code RT for spindle position and orientation."; RL Nat. Cell Biol. 14:311-317(2012). RN [26] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=23386061; DOI=10.1038/emboj.2013.3; RA Kodani A., Salome Sirerol-Piquer M., Seol A., Garcia-Verdugo J.M., RA Reiter J.F.; RT "Kif3a interacts with Dynactin subunit p150 Glued to organize centriole RT subdistal appendages."; RL EMBO J. 32:597-607(2013). RN [27] RP INTERACTION WITH MISP. RX PubMed=23509069; DOI=10.1083/jcb.201207050; RA Zhu M., Settele F., Kotak S., Sanchez-Pulido L., Ehret L., Ponting C.P., RA Goenczy P., Hoffmann I.; RT "MISP is a novel Plk1 substrate required for proper spindle orientation and RT mitotic progression."; RL J. Cell Biol. 200:773-787(2013). RN [28] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [29] RP PHOSPHORYLATION AT THR-145; THR-146 AND THR-147, SUBCELLULAR LOCATION, AND RP MUTAGENESIS OF THR-145; THR-146 AND THR-147. RX PubMed=23985322; DOI=10.1091/mbc.e13-03-0137; RA Zhapparova O.N., Fokin A.I., Vorobyeva N.E., Bryantseva S.A., RA Nadezhdina E.S.; RT "Ste20-like protein kinase SLK (LOSK) regulates microtubule organization by RT targeting dynactin to the centrosome."; RL Mol. Biol. Cell 24:3205-3214(2013). RN [30] RP INTERACTION WITH CEP126. RX PubMed=24867236; DOI=10.1111/boc.201300087; RA Bonavita R., Walas D., Brown A.K., Luini A., Stephens D.J., Colanzi A.; RT "Cep126 is required for pericentriolar satellite localisation to the RT centrosome and for primary cilium formation."; RL Biol. Cell 106:254-267(2014). RN [31] RP INTERACTION WITH HPS6. RX PubMed=25189619; DOI=10.1242/jcs.141978; RA Li K., Yang L., Zhang C., Niu Y., Li W., Liu J.J.; RT "HPS6 interacts with dynactin p150Glued to mediate retrograde trafficking RT and maturation of lysosomes."; RL J. Cell Sci. 127:4574-4588(2014). RN [32] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [33] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=25774020; DOI=10.1002/jcb.25160; RA Chen T.Y., Syu J.S., Han T.Y., Cheng H.L., Lu F.I., Wang C.Y.; RT "Cell cycle-dependent localization of dynactin subunit p150 glued at RT centrosome."; RL J. Cell. Biochem. 116:2049-2060(2015). RN [34] RP ASSOCIATION WITH MICROTUBULES, AND DOMAIN CAP-GLY. RX PubMed=26968983; DOI=10.15252/embj.201593071; RA McKenney R.J., Huynh W., Vale R.D., Sirajuddin M.; RT "Tyrosination of alpha-tubulin controls the initiation of processive RT dynein-dynactin motility."; RL EMBO J. 35:1175-1185(2016). RN [35] RP INTERACTION WITH BCCIP. RX PubMed=28394342; DOI=10.1038/onc.2017.92; RA Huhn S.C., Liu J., Ye C., Lu H., Jiang X., Feng X., Ganesan S., White E., RA Shen Z.; RT "Regulation of spindle integrity and mitotic fidelity by BCCIP."; RL Oncogene 36:4750-4766(2017). RN [36] RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 15-107 IN COMPLEX WITH MAPRE1, RP AND INTERACTION WITH MAPRE1. RX PubMed=16109370; DOI=10.1016/j.molcel.2005.06.034; RA Hayashi I., Wilde A., Mal T.K., Ikura M.; RT "Structural basis for the activation of microtubule assembly by the EB1 and RT p150Glued complex."; RL Mol. Cell 19:449-460(2005). RN [37] RP STRUCTURE BY NMR OF 1-99. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the CAP-Gly domain in human dynactin 1."; RL Submitted (NOV-2005) to the PDB data bank. RN [38] RP X-RAY CRYSTALLOGRAPHY (1.86 ANGSTROMS) OF 18-111 IN COMPLEX WITH MAPRE1, RP AND INTERACTION WITH MAPRE1. RX PubMed=16949363; DOI=10.1016/j.molcel.2006.07.013; RA Honnappa S., Okhrimenko O., Jaussi R., Jawhari H., Jelesarov I., RA Winkler F.K., Steinmetz M.O.; RT "Key interaction modes of dynamic +TIP networks."; RL Mol. Cell 23:663-671(2006). RN [39] RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 15-111 IN COMPLEX WITH CLIP1, RP SUBCELLULAR LOCATION, AND INTERACTION WITH CLIP1. RX PubMed=17828277; DOI=10.1038/nsmb1291; RA Weisbrich A., Honnappa S., Jaussi R., Okhrimenko O., Frey D., Jelesarov I., RA Akhmanova A., Steinmetz M.O.; RT "Structure-function relationship of CAP-Gly domains."; RL Nat. Struct. Mol. Biol. 14:959-967(2007). RN [40] RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 15-107 IN COMPLEX WITH CLIP1, RP INTERACTION WITH CLIP1, AND MUTAGENESIS OF LYS-68 AND ARG-90. RX PubMed=17828275; DOI=10.1038/nsmb1299; RA Hayashi I., Plevin M.J., Ikura M.; RT "CLIP170 autoinhibition mimics intermolecular interactions with p150Glued RT or EB1."; RL Nat. Struct. Mol. Biol. 14:980-981(2007). RN [41] RP VARIANT HMND14 SER-59. RX PubMed=12627231; DOI=10.1038/ng1123; RA Puls I., Jonnakuty C., LaMonte B.H., Holzbaur E.L., Tokito M., Mann E., RA Floeter M.K., Bidus K., Drayna D., Oh S.J., Brown R.H. Jr., Ludlow C.L., RA Fischbeck K.H.; RT "Mutant dynactin in motor neuron disease."; RL Nat. Genet. 33:455-456(2003). RN [42] RP INVOLVEMENT IN ALS, AND VARIANTS ALS THR-571; TRP-785 AND ILE-1249. RX PubMed=15326253; DOI=10.1212/01.wnl.0000134608.83927.b1; RA Muench C., Sedlmeier R., Meyer T., Homberg V., Sperfeld A.D., Kurt A., RA Prudlo J., Peraus G., Hanemann C.O., Stumm G., Ludolph A.C.; RT "Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS."; RL Neurology 63:724-726(2004). RN [43] RP VARIANT ALS LYS-1101. RX PubMed=16240349; DOI=10.1002/ana.20631; RA Muench C., Rosenbohm A., Sperfeld A.-D., Uttner I., Reske S., Krause B.J., RA Sedlmeier R., Meyer T., Hanemann C.O., Stumm G., Ludolph A.C.; RT "Heterozygous R1101K mutation of the DCTN1 gene in a family with ALS and RT FTD."; RL Ann. Neurol. 58:777-780(2005). RN [44] RP CHARACTERIZATION OF VARIANT HMND14 SER-59, AND INTERACTION WITH MAPRE1. RX PubMed=16505168; DOI=10.1083/jcb.200511068; RA Levy J.R., Sumner C.J., Caviston J.P., Tokito M.K., Ranganathan S., RA Ligon L.A., Wallace K.E., LaMonte B.H., Harmison G.G., Puls I., RA Fischbeck K.H., Holzbaur E.L.F.; RT "A motor neuron disease-associated mutation in p150Glued perturbs dynactin RT function and induces protein aggregation."; RL J. Cell Biol. 172:733-745(2006). RN [45] RP VARIANTS VAL-196; GLN-495 AND ILE-1249. RX PubMed=17824900; DOI=10.1111/j.1600-0404.2007.00884.x; RA Muench C., Meyer R., Linke P., Meyer T., Ludolph A.C., Haas J., Hemmer B.; RT "The p150 subunit of dynactin (DCTN1) gene in multiple sclerosis."; RL Acta Neurol. Scand. 116:231-234(2007). RN [46] RP VARIANTS PERRYS ARG-71; GLU-71; ALA-71; PRO-72 AND PRO-74, CHARACTERIZATION RP OF VARIANTS PERRYS ARG-71 AND PRO-74, AND CHARACTERIZATION OF VARIANT RP HMND14 SER-59. RX PubMed=19136952; DOI=10.1038/ng.293; RA Farrer M.J., Hulihan M.M., Kachergus J.M., Daechsel J.C., Stoessl A.J., RA Grantier L.L., Calne S., Calne D.B., Lechevalier B., Chapon F., Tsuboi Y., RA Yamada T., Gutmann L., Elibol B., Bhatia K.P., Wider C., RA Vilarino-Gueell C., Ross O.A., Brown L.A., Castanedes-Casey M., RA Dickson D.W., Wszolek Z.K.; RT "DCTN1 mutations in Perry syndrome."; RL Nat. Genet. 41:163-165(2009). RN [47] RP VARIANT ILE-1249. RX PubMed=19506225; DOI=10.1212/wnl.0b013e3181a92c4c; RA Vilarino-Gueell C., Wider C., Soto-Ortolaza A.I., Cobb S.A., RA Kachergus J.M., Keeling B.H., Dachsel J.C., Hulihan M.M., Dickson D.W., RA Wszolek Z.K., Uitti R.J., Graff-Radford N.R., Boeve B.F., Josephs K.A., RA Miller B., Boylan K.B., Gwinn K., Adler C.H., Aasly J.O., Hentati F., RA Destee A., Krygowska-Wajs A., Chartier-Harlin M.-C., Ross O.A., RA Rademakers R., Farrer M.J.; RT "Characterization of DCTN1 genetic variability in neurodegeneration."; RL Neurology 72:2024-2028(2009). RN [48] RP CHARACTERIZATION OF VARIANT HMND14 SER-59. RX PubMed=19279216; DOI=10.1073/pnas.0810828106; RA Moore J.K., Sept D., Cooper J.A.; RT "Neurodegeneration mutations in dynactin impair dynein-dependent nuclear RT migration."; RL Proc. Natl. Acad. Sci. U.S.A. 106:5147-5152(2009). RN [49] RP CHARACTERIZATION OF VARIANT HMND14 SER-59, CHARACTERIZATION OF VARIANT RP 196-ILE, INTERACTION WITH TBCB, AND SUBCELLULAR LOCATION. RX PubMed=22777741; DOI=10.1007/s00441-012-1463-z; RA Kuh G.F., Stockmann M., Meyer-Ohlendorf M., Linta L., Proepper C., RA Ludolph A.C., Bockmann J., Boeckers T.M., Liebau S.; RT "Tubulin-binding cofactor B is a direct interaction partner of the dynactin RT subunit p150(Glued)."; RL Cell Tissue Res. 350:13-26(2012). RN [50] RP CHARACTERIZATION OF VARIANT PERRYS PRO-74, FUNCTION, SUBUNIT, AND RP INTERACTION WITH MAPRE1. RX PubMed=23874158; DOI=10.1371/journal.pbio.1001611; RA Lazarus J.E., Moughamian A.J., Tokito M.K., Holzbaur E.L.; RT "Dynactin subunit p150(Glued) is a neuron-specific anti-catastrophe RT factor."; RL PLoS Biol. 11:E1001611-E1001611(2013). RN [51] RP VARIANT PHE-670. RX PubMed=24627108; DOI=10.1007/s00415-014-7289-8; RA Schabhuettl M., Wieland T., Senderek J., Baets J., Timmerman V., RA De Jonghe P., Reilly M.M., Stieglbauer K., Laich E., Windhager R., Erwa W., RA Trajanoski S., Strom T.M., Auer-Grumbach M.; RT "Whole-exome sequencing in patients with inherited neuropathies: outcome RT and challenges."; RL J. Neurol. 261:970-982(2014). RN [52] RP VARIANT PERRYS LEU-52. RX PubMed=24676999; DOI=10.1002/mds.25833; RA Araki E., Tsuboi Y., Daechsel J., Milnerwood A., Vilarino-Guell C., RA Fujii N., Mishima T., Oka T., Hara H., Fukae J., Farrer M.J.; RT "A Novel DCTN1 mutation with late-onset parkinsonism and frontotemporal RT atrophy."; RL Mov. Disord. 29:1201-1204(2014). RN [53] RP CHARACTERIZATION OF VARIANTS PERRYS ARG-71 AND PRO-74, FUNCTION, RP INTERACTION WITH DYNEIN INTERMEDIATE CHAIN AND DYNEIN HEAVY CHAIN, AND RP DOMAIN CAP-GLY. RX PubMed=25185702; DOI=10.1038/ncomms5807; RA Ayloo S., Lazarus J.E., Dodda A., Tokito M., Ostap E.M., Holzbaur E.L.; RT "Dynactin functions as both a dynamic tether and brake during dynein-driven RT motility."; RL Nat. Commun. 5:4807-4807(2014). RN [54] RP VARIANTS PERRYS ARG-71 AND CYS-78, AND CHARACTERIZATION OF VARIANTS PERRYS RP ARG-71 AND CYS-78. RX PubMed=24881494; DOI=10.1016/j.parkreldis.2014.05.004; RA Tacik P., Fiesel F.C., Fujioka S., Ross O.A., Pretelt F., RA Castaneda Cardona C., Kidd A., Hlavac M., Raizis A., Okun M.S., Traynor S., RA Strongosky A.J., Springer W., Wszolek Z.K.; RT "Three families with Perry syndrome from distinct parts of the world."; RL Parkinsonism Relat. Disord. 20:884-888(2014). RN [55] RP CHARACTERIZATION OF VARIANT PERRYS ARG-71, SUBCELLULAR LOCATION, DOMAIN RP CAP-GLY, INTERACTION WITH CLIP1, AND ASSOCIATION WITH MICROTUBULES. RX PubMed=26972003; DOI=10.1016/j.celrep.2016.02.046; RA Nirschl J.J., Magiera M.M., Lazarus J.E., Janke C., Holzbaur E.L.; RT "Alpha-tubulin tyrosination and CLIP-170 phosphorylation regulate the RT initiation of dynein-driven transport in neurons."; RL Cell Rep. 14:2637-2652(2016). RN [56] RP INTERACTION WITH RUFY3 AND RUFY4. RX PubMed=35314674; DOI=10.1038/s41467-022-28952-y; RA Keren-Kaplan T., Saric A., Ghosh S., Williamson C.D., Jia R., Li Y., RA Bonifacino J.S.; RT "RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes RT to dynein-dynactin."; RL Nat. Commun. 13:1506-1506(2022). CC -!- FUNCTION: Part of the dynactin complex that activates the molecular CC motor dynein for ultra-processive transport along microtubules (By CC similarity). Plays a key role in dynein-mediated retrograde transport CC of vesicles and organelles along microtubules by recruiting and CC tethering dynein to microtubules. Binds to both dynein and microtubules CC providing a link between specific cargos, microtubules and dynein. CC Essential for targeting dynein to microtubule plus ends, recruiting CC dynein to membranous cargos and enhancing dynein processivity (the CC ability to move along a microtubule for a long distance without falling CC off the track). Can also act as a brake to slow the dynein motor during CC motility along the microtubule (PubMed:25185702). Can regulate CC microtubule stability by promoting microtubule formation, nucleation CC and polymerization and by inhibiting microtubule catastrophe in CC neurons. Inhibits microtubule catastrophe by binding both to CC microtubules and to tubulin, leading to enhanced microtubule stability CC along the axon (PubMed:23874158). Plays a role in metaphase spindle CC orientation (PubMed:22327364). Plays a role in centriole cohesion and CC subdistal appendage organization and function. Its recruitment to the CC centriole in a KIF3A-dependent manner is essential for the maintenance CC of centriole cohesion and the formation of subdistal appendage. Also CC required for microtubule anchoring at the mother centriole CC (PubMed:23386061). Plays a role in primary cilia formation CC (PubMed:25774020). {ECO:0000250|UniProtKB:A0A287B8J2, CC ECO:0000269|PubMed:22327364, ECO:0000269|PubMed:23386061, CC ECO:0000269|PubMed:23874158, ECO:0000269|PubMed:25185702, CC ECO:0000269|PubMed:25774020}. CC -!- SUBUNIT: Monomer and homodimer (PubMed:23874158). Subunit of dynactin, CC a multiprotein complex part of a tripartite complex with dynein and a CC adapter, such as BICDL1, BICD2 or HOOK3. The dynactin complex is built CC around ACTR1A/ACTB filament and consists of an actin-related filament CC composed of a shoulder domain, a pointed end and a barbed end. Its CC length is defined by its flexible shoulder domain. The soulder is CC composed of 2 DCTN1 subunits, 4 DCTN2 and 2 DCTN3. DCTN1/p150(glued) CC binds directly to microtubules and to cytoplasmic dynein. The 4 DCNT2 CC (via N-terminus) bind the ACTR1A filament and act as molecular rulers CC to determine the length. The pointed end is important for binding CC dynein-dynactin cargo adapters. Consists of 4 subunits: ACTR10, DCNT4, CC DCTN5 and DCTN6. The barbed end is composed of a CAPZA1:CAPZB CC heterodimers, which binds ACTR1A/ACTB filament and dynactin and CC stabilizes dynactin (By similarity). Interacts with the C-terminus of CC MAPRE1, MAPRE2 and MAPRE3. Interacts (via C-terminus) with SNX6. CC Interacts with CLN3, DYNAP, ECPAS and FBXL5. Interacts with MISP; this CC interaction regulates its distribution at the cell cortex. Interacts CC with CEP131. Interacts with CEP126 (PubMed:24867236). Interacts with CC CLIP1 (PubMed:17828275, PubMed:17828277, PubMed:20679239, CC PubMed:26972003). Interacts with dynein intermediate chain and dynein CC heavy chain (PubMed:25185702). Interacts with PLK1 (via POLO-box CC domain) (PubMed:20679239). Interacts with TBCB (PubMed:22777741). Binds CC preferentially to tyrosinated microtubules than to detyrosinated CC microtubules (PubMed:26968983, PubMed:26972003). Interacts with PARD6A CC (PubMed:20719959). Interacts with HPS6 (PubMed:25189619). Interacts CC with KIF3A. Interacts with BICD2 (By similarity). Interacts with DST CC (isoform 9) (By similarity). Interacts with DST (isoform 1) (By CC similarity). Identified in a complex with MREG and RILP (By CC similarity). Interacts with BCCIP (isoform 2/alpha) (PubMed:28394342). CC Interacts with DCDC1 (PubMed:22159412). Interacts with AKNA (By CC similarity). Interacts with DYNC1I2 (By similarity). Interacts with CC RUFY3 and RUFY4 (PubMed:35314674). {ECO:0000250|UniProtKB:A0A287B8J2, CC ECO:0000250|UniProtKB:O08788, ECO:0000269|PubMed:14514668, CC ECO:0000269|PubMed:16109370, ECO:0000269|PubMed:16505168, CC ECO:0000269|PubMed:16949363, ECO:0000269|PubMed:17532294, CC ECO:0000269|PubMed:17828275, ECO:0000269|PubMed:17828277, CC ECO:0000269|PubMed:19935774, ECO:0000269|PubMed:20679239, CC ECO:0000269|PubMed:20682791, ECO:0000269|PubMed:20719959, CC ECO:0000269|PubMed:20978158, ECO:0000269|PubMed:22159412, CC ECO:0000269|PubMed:22261744, ECO:0000269|PubMed:22777741, CC ECO:0000269|PubMed:22797915, ECO:0000269|PubMed:23509069, CC ECO:0000269|PubMed:23874158, ECO:0000269|PubMed:24867236, CC ECO:0000269|PubMed:25185702, ECO:0000269|PubMed:25189619, CC ECO:0000269|PubMed:26968983, ECO:0000269|PubMed:26972003, CC ECO:0000269|PubMed:28394342, ECO:0000269|PubMed:35314674}. CC -!- INTERACTION: CC Q14203; Q9NZ32: ACTR10; NbExp=7; IntAct=EBI-724352, EBI-2559426; CC Q14203; P61163: ACTR1A; NbExp=8; IntAct=EBI-724352, EBI-774234; CC Q14203; P42025: ACTR1B; NbExp=6; IntAct=EBI-724352, EBI-367493; CC Q14203; Q96RK4: BBS4; NbExp=3; IntAct=EBI-724352, EBI-1805814; CC Q14203; P52907: CAPZA1; NbExp=3; IntAct=EBI-724352, EBI-355586; CC Q14203; P47756: CAPZB; NbExp=7; IntAct=EBI-724352, EBI-353595; CC Q14203; P30622-1: CLIP1; NbExp=7; IntAct=EBI-724352, EBI-9640673; CC Q14203; Q13561: DCTN2; NbExp=9; IntAct=EBI-724352, EBI-715074; CC Q14203; O75935: DCTN3; NbExp=7; IntAct=EBI-724352, EBI-347442; CC Q14203; Q9UJW0: DCTN4; NbExp=7; IntAct=EBI-724352, EBI-2134033; CC Q14203; O00399: DCTN6; NbExp=9; IntAct=EBI-724352, EBI-2559415; CC Q14203; Q15691: MAPRE1; NbExp=9; IntAct=EBI-724352, EBI-1004115; CC Q14203; P10636-8: MAPT; NbExp=9; IntAct=EBI-724352, EBI-366233; CC Q14203; Q9UNH7: SNX6; NbExp=2; IntAct=EBI-724352, EBI-949294; CC Q14203; P54256: Hap1; Xeno; NbExp=4; IntAct=EBI-724352, EBI-994539; CC Q14203-5; Q6ZTN6-2: ANKRD13D; NbExp=3; IntAct=EBI-25840379, EBI-25840993; CC Q14203-5; P63010-2: AP2B1; NbExp=3; IntAct=EBI-25840379, EBI-11529439; CC Q14203-5; P05067: APP; NbExp=5; IntAct=EBI-25840379, EBI-77613; CC Q14203-5; O95671: ASMTL; NbExp=3; IntAct=EBI-25840379, EBI-743231; CC Q14203-5; P18847: ATF3; NbExp=3; IntAct=EBI-25840379, EBI-712767; CC Q14203-5; P46379-2: BAG6; NbExp=3; IntAct=EBI-25840379, EBI-10988864; CC Q14203-5; Q8NFJ9: BBS1; NbExp=3; IntAct=EBI-25840379, EBI-1805484; CC Q14203-5; O15392: BIRC5; NbExp=3; IntAct=EBI-25840379, EBI-518823; CC Q14203-5; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-25840379, EBI-2837444; CC Q14203-5; P42574: CASP3; NbExp=3; IntAct=EBI-25840379, EBI-524064; CC Q14203-5; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-25840379, EBI-350590; CC Q14203-5; O75935-2: DCTN3; NbExp=3; IntAct=EBI-25840379, EBI-12091947; CC Q14203-5; O60479: DLX3; NbExp=3; IntAct=EBI-25840379, EBI-3908248; CC Q14203-5; O14576-2: DYNC1I1; NbExp=3; IntAct=EBI-25840379, EBI-25840445; CC Q14203-5; Q8TC29: ENKUR; NbExp=3; IntAct=EBI-25840379, EBI-9246952; CC Q14203-5; Q6NXG1: ESRP1; NbExp=3; IntAct=EBI-25840379, EBI-10213520; CC Q14203-5; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-25840379, EBI-396453; CC Q14203-5; Q9UBN7: HDAC6; NbExp=6; IntAct=EBI-25840379, EBI-301697; CC Q14203-5; Q8IY31-3: IFT20; NbExp=3; IntAct=EBI-25840379, EBI-9091197; CC Q14203-5; Q6DN90-2: IQSEC1; NbExp=3; IntAct=EBI-25840379, EBI-21911304; CC Q14203-5; Q96EK5: KIFBP; NbExp=3; IntAct=EBI-25840379, EBI-744150; CC Q14203-5; Q9Y2M5: KLHL20; NbExp=3; IntAct=EBI-25840379, EBI-714379; CC Q14203-5; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-25840379, EBI-11985629; CC Q14203-5; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-25840379, EBI-1108377; CC Q14203-5; O95777: LSM8; NbExp=3; IntAct=EBI-25840379, EBI-347779; CC Q14203-5; P43360: MAGEA6; NbExp=3; IntAct=EBI-25840379, EBI-1045155; CC Q14203-5; P10636-6: MAPT; NbExp=3; IntAct=EBI-25840379, EBI-7796455; CC Q14203-5; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-25840379, EBI-21250407; CC Q14203-5; Q8N594: MPND; NbExp=3; IntAct=EBI-25840379, EBI-2512452; CC Q14203-5; O15381-5: NVL; NbExp=3; IntAct=EBI-25840379, EBI-18577082; CC Q14203-5; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-25840379, EBI-1058491; CC Q14203-5; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-25840379, EBI-25830200; CC Q14203-5; Q9BR81: PCDHGC3; NbExp=3; IntAct=EBI-25840379, EBI-22012354; CC Q14203-5; Q9NV79: PCMTD2; NbExp=3; IntAct=EBI-25840379, EBI-6309018; CC Q14203-5; P17980: PSMC3; NbExp=3; IntAct=EBI-25840379, EBI-359720; CC Q14203-5; Q9UJ41-4: RABGEF1; NbExp=3; IntAct=EBI-25840379, EBI-14093916; CC Q14203-5; Q9ULX5: RNF112; NbExp=3; IntAct=EBI-25840379, EBI-25829984; CC Q14203-5; Q8IYW5: RNF168; NbExp=3; IntAct=EBI-25840379, EBI-914207; CC Q14203-5; Q96D59: RNF183; NbExp=3; IntAct=EBI-25840379, EBI-743938; CC Q14203-5; Q92834-6: RPGR; NbExp=3; IntAct=EBI-25840379, EBI-16431517; CC Q14203-5; Q8N488: RYBP; NbExp=3; IntAct=EBI-25840379, EBI-752324; CC Q14203-5; Q15436: SEC23A; NbExp=3; IntAct=EBI-25840379, EBI-81088; CC Q14203-5; Q9GZS3: SKIC8; NbExp=3; IntAct=EBI-25840379, EBI-358545; CC Q14203-5; Q9HCE7-2: SMURF1; NbExp=3; IntAct=EBI-25840379, EBI-9845742; CC Q14203-5; Q99932-2: SPAG8; NbExp=3; IntAct=EBI-25840379, EBI-11959123; CC Q14203-5; O75886: STAM2; NbExp=3; IntAct=EBI-25840379, EBI-373258; CC Q14203-5; Q15554-4: TERF2; NbExp=3; IntAct=EBI-25840379, EBI-25840535; CC Q14203-5; Q71RG4-4: TMUB2; NbExp=3; IntAct=EBI-25840379, EBI-25831574; CC Q14203-5; Q9H0E2: TOLLIP; NbExp=3; IntAct=EBI-25840379, EBI-74615; CC Q14203-5; P19474: TRIM21; NbExp=3; IntAct=EBI-25840379, EBI-81290; CC Q14203-5; Q8WVJ9: TWIST2; NbExp=3; IntAct=EBI-25840379, EBI-1797313; CC Q14203-5; P62987: UBA52; NbExp=3; IntAct=EBI-25840379, EBI-357304; CC Q14203-5; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-25840379, EBI-749370; CC Q14203-5; Q8NBM4-4: UBAC2; NbExp=3; IntAct=EBI-25840379, EBI-25840976; CC Q14203-5; P57075-2: UBASH3A; NbExp=3; IntAct=EBI-25840379, EBI-7353612; CC Q14203-5; Q04323-2: UBXN1; NbExp=3; IntAct=EBI-25840379, EBI-11530712; CC Q14203-5; Q96RL1-2: UIMC1; NbExp=3; IntAct=EBI-25840379, EBI-17761788; CC Q14203-5; O00308: WWP2; NbExp=3; IntAct=EBI-25840379, EBI-743923; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:17828277}. CC Cytoplasm, cytoskeleton {ECO:0000269|PubMed:17828277, CC ECO:0000269|PubMed:22777741, ECO:0000269|PubMed:25774020, CC ECO:0000269|PubMed:26972003}. Cytoplasm, cytoskeleton, microtubule CC organizing center, centrosome {ECO:0000269|PubMed:14654843, CC ECO:0000269|PubMed:20719959, ECO:0000269|PubMed:23985322, CC ECO:0000269|PubMed:25774020}. Cytoplasm, cytoskeleton, microtubule CC organizing center, centrosome, centriole {ECO:0000269|PubMed:23386061, CC ECO:0000269|PubMed:25774020}. Cytoplasm, cytoskeleton, spindle CC {ECO:0000269|PubMed:25774020}. Nucleus envelope CC {ECO:0000269|PubMed:20679239}. Cytoplasm, cell cortex CC {ECO:0000269|PubMed:22327364}. Note=Localizes to microtubule plus ends CC (PubMed:17828277, PubMed:22777741, PubMed:25774020). Localizes CC preferentially to the ends of tyrosinated microtubules CC (PubMed:26972003). Localization at centrosome is regulated by SLK- CC dependent phosphorylation (PubMed:23985322). Localizes to centrosome in CC a PARKDA-dependent manner (PubMed:20719959). Localizes to the subdistal CC appendage region of the centriole in a KIF3A-dependent manner CC (PubMed:23386061). PLK1-mediated phosphorylation at Ser-179 is CC essential for its localization in the nuclear envelope CC (PubMed:20679239). {ECO:0000269|PubMed:17828277, CC ECO:0000269|PubMed:20679239, ECO:0000269|PubMed:20719959, CC ECO:0000269|PubMed:22777741, ECO:0000269|PubMed:23386061, CC ECO:0000269|PubMed:23985322, ECO:0000269|PubMed:25774020, CC ECO:0000269|PubMed:26972003}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; CC Name=p150; CC IsoId=Q14203-1; Sequence=Displayed; CC Name=p135; CC IsoId=Q14203-2; Sequence=VSP_000760; CC Name=3; CC IsoId=Q14203-3; Sequence=VSP_045392, VSP_045393, VSP_045394; CC Name=4; CC IsoId=Q14203-4; Sequence=VSP_045393, VSP_045394; CC Name=5; CC IsoId=Q14203-5; Sequence=VSP_000760, VSP_045394; CC Name=6; CC IsoId=Q14203-6; Sequence=VSP_047174; CC -!- TISSUE SPECIFICITY: Brain. CC -!- DOMAIN: The CAP-Gly domain is essential for interactions with CC microtubules and its binding partners and for its motion along the CC microtubules. Essential for its preferential binding to tyrosinated CC microtubules and for promoting the sustained interaction of the dynein CC motor with microtubules. {ECO:0000269|PubMed:25185702, CC ECO:0000269|PubMed:26968983, ECO:0000269|PubMed:26972003}. CC -!- PTM: Ubiquitinated by a SCF complex containing FBXL5, leading to its CC degradation by the proteasome. {ECO:0000269|PubMed:17532294}. CC -!- PTM: Phosphorylation by SLK at Thr-145, Thr-146 and Thr-147 targets CC DCTN1 to the centrosome. It is uncertain if SLK phosphorylates all CC three threonines or one or two of them. PLK1-mediated phosphorylation CC at Ser-179 is essential for its localization in the nuclear envelope, CC promotes its dissociation from microtubules during early mitosis and CC positively regulates nuclear envelope breakdown during prophase. CC {ECO:0000269|PubMed:20679239, ECO:0000269|PubMed:23985322}. CC -!- DISEASE: Neuronopathy, distal hereditary motor, autosomal dominant 14 CC (HMND14) [MIM:607641]: A form of distal hereditary motor neuronopathy, CC a heterogeneous group of neuromuscular disorders caused by selective CC degeneration of motor neurons in the anterior horn of the spinal cord, CC without sensory deficit in the posterior horn. The overall clinical CC picture consists of a classical distal muscular atrophy syndrome in the CC legs without clinical sensory loss. The disease starts with weakness CC and wasting of distal muscles of the anterior tibial and peroneal CC compartments of the legs. Later on, weakness and atrophy may expand to CC the proximal muscles of the lower limbs and/or to the distal upper CC limbs. {ECO:0000269|PubMed:12627231, ECO:0000269|PubMed:16505168, CC ECO:0000269|PubMed:19136952, ECO:0000269|PubMed:19279216, CC ECO:0000269|PubMed:22777741}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Amyotrophic lateral sclerosis (ALS) [MIM:105400]: A CC neurodegenerative disorder affecting upper motor neurons in the brain CC and lower motor neurons in the brain stem and spinal cord, resulting in CC fatal paralysis. Sensory abnormalities are absent. The pathologic CC hallmarks of the disease include pallor of the corticospinal tract due CC to loss of motor neurons, presence of ubiquitin-positive inclusions CC within surviving motor neurons, and deposition of pathologic CC aggregates. The etiology of amyotrophic lateral sclerosis is likely to CC be multifactorial, involving both genetic and environmental factors. CC The disease is inherited in 5-10% of the cases. CC {ECO:0000269|PubMed:15326253, ECO:0000269|PubMed:16240349}. CC Note=Disease susceptibility is associated with variants affecting the CC gene represented in this entry. CC -!- DISEASE: Perry syndrome (PERRYS) [MIM:168605]: A neuropsychiatric CC disorder characterized by mental depression not responsive to CC antidepressant drugs or electroconvulsive therapy, sleep disturbances, CC exhaustion and marked weight loss. Parkinsonism develops later and CC respiratory failure occurred terminally. {ECO:0000269|PubMed:19136952, CC ECO:0000269|PubMed:23874158, ECO:0000269|PubMed:24676999, CC ECO:0000269|PubMed:24881494, ECO:0000269|PubMed:25185702, CC ECO:0000269|PubMed:26972003}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the dynactin 150 kDa subunit family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF064205; AAD55811.1; -; Genomic_DNA. DR EMBL; AF064203; AAD55811.1; JOINED; Genomic_DNA. DR EMBL; AF064204; AAD55811.1; JOINED; Genomic_DNA. DR EMBL; AF064205; AAD55812.1; -; Genomic_DNA. DR EMBL; AF064204; AAD55812.1; JOINED; Genomic_DNA. DR EMBL; AK297286; BAG59757.1; -; mRNA. DR EMBL; AK314352; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AC005041; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471053; EAW99684.1; -; Genomic_DNA. DR EMBL; BC071583; AAH71583.1; -; mRNA. DR EMBL; X98801; CAA67333.1; -; mRNA. DR EMBL; AF086947; AAD03694.1; -; Genomic_DNA. DR EMBL; AF086927; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086928; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086929; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086930; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086931; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086932; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086933; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086934; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086935; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086936; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086937; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086938; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086939; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086940; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086941; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086942; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086943; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086944; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086945; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; AF086946; AAD03694.1; JOINED; Genomic_DNA. DR EMBL; BT006758; AAP35404.1; -; mRNA. DR CCDS; CCDS1939.1; -. [Q14203-1] DR CCDS; CCDS46341.1; -. [Q14203-4] DR CCDS; CCDS46342.1; -. [Q14203-5] DR CCDS; CCDS46343.1; -. [Q14203-2] DR CCDS; CCDS54368.1; -. [Q14203-3] DR CCDS; CCDS54369.1; -. [Q14203-6] DR RefSeq; NP_001128512.1; NM_001135040.3. [Q14203-4] DR RefSeq; NP_001128513.1; NM_001135041.3. [Q14203-5] DR RefSeq; NP_001177765.1; NM_001190836.2. [Q14203-3] DR RefSeq; NP_001177766.1; NM_001190837.2. [Q14203-6] DR RefSeq; NP_004073.2; NM_004082.4. [Q14203-1] DR RefSeq; NP_075408.1; NM_023019.4. [Q14203-2] DR PDB; 1TXQ; X-ray; 1.80 A; A=15-107. DR PDB; 2COY; NMR; -; A=1-99. DR PDB; 2HKN; X-ray; 1.87 A; A/B=18-111. DR PDB; 2HKQ; X-ray; 1.86 A; B=18-111. DR PDB; 2HL3; X-ray; 2.03 A; A/B=18-111. DR PDB; 2HL5; X-ray; 1.93 A; C/D=18-111. DR PDB; 2HQH; X-ray; 1.80 A; A/B/C/D=15-107. DR PDB; 3E2U; X-ray; 2.60 A; A/B/C/D=18-111. DR PDB; 3TQ7; X-ray; 2.30 A; P/Q=27-97. DR PDB; 9B7J; EM; 3.49 A; S/s=1-1278. DR PDBsum; 1TXQ; -. DR PDBsum; 2COY; -. DR PDBsum; 2HKN; -. DR PDBsum; 2HKQ; -. DR PDBsum; 2HL3; -. DR PDBsum; 2HL5; -. DR PDBsum; 2HQH; -. DR PDBsum; 3E2U; -. DR PDBsum; 3TQ7; -. DR PDBsum; 9B7J; -. DR AlphaFoldDB; Q14203; -. DR BMRB; Q14203; -. DR EMDB; EMD-2673; -. DR EMDB; EMD-2674; -. DR EMDB; EMD-2675; -. DR EMDB; EMD-44306; -. DR SMR; Q14203; -. DR BioGRID; 108007; 502. DR ComplexPortal; CPX-26352; Dynactin complex. DR CORUM; Q14203; -. DR DIP; DIP-31365N; -. DR FunCoup; Q14203; 1563. DR IntAct; Q14203; 326. DR MINT; Q14203; -. DR STRING; 9606.ENSP00000354791; -. DR CarbonylDB; Q14203; -. DR GlyCosmos; Q14203; 1 site, 1 glycan. DR GlyGen; Q14203; 3 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q14203; -. DR MetOSite; Q14203; -. DR PhosphoSitePlus; Q14203; -. DR SwissPalm; Q14203; -. DR BioMuta; DCTN1; -. DR DMDM; 17375490; -. DR OGP; Q14203; -. DR jPOST; Q14203; -. DR MassIVE; Q14203; -. DR PaxDb; 9606-ENSP00000354791; -. DR PeptideAtlas; Q14203; -. DR ProteomicsDB; 20166; -. DR ProteomicsDB; 20302; -. DR ProteomicsDB; 2371; -. DR ProteomicsDB; 33940; -. DR ProteomicsDB; 59925; -. [Q14203-1] DR ProteomicsDB; 59926; -. [Q14203-2] DR Pumba; Q14203; -. DR ABCD; Q14203; 1 sequenced antibody. DR Antibodypedia; 3966; 328 antibodies from 41 providers. DR DNASU; 1639; -. DR Ensembl; ENST00000394003.7; ENSP00000377571.3; ENSG00000204843.14. [Q14203-6] DR Ensembl; ENST00000409240.5; ENSP00000386406.1; ENSG00000204843.14. [Q14203-3] DR Ensembl; ENST00000409438.5; ENSP00000387270.1; ENSG00000204843.14. [Q14203-5] DR Ensembl; ENST00000409567.7; ENSP00000386843.3; ENSG00000204843.14. [Q14203-4] DR Ensembl; ENST00000628224.3; ENSP00000487279.2; ENSG00000204843.14. [Q14203-1] DR Ensembl; ENST00000633691.1; ENSP00000487724.1; ENSG00000204843.14. [Q14203-2] DR GeneID; 1639; -. DR KEGG; hsa:1639; -. DR MANE-Select; ENST00000628224.3; ENSP00000487279.2; NM_004082.5; NP_004073.2. DR UCSC; uc002sku.4; human. [Q14203-1] DR AGR; HGNC:2711; -. DR ClinPGx; PA27180; -. DR CTD; 1639; -. DR DisGeNET; 1639; -. DR GeneCards; DCTN1; -. DR GeneReviews; DCTN1; -. DR HGNC; HGNC:2711; DCTN1. DR HPA; ENSG00000204843; Low tissue specificity. DR MalaCards; DCTN1; -. DR MIM; 105400; phenotype. DR MIM; 168605; phenotype. DR MIM; 601143; gene. DR MIM; 607641; phenotype. DR OpenTargets; ENSG00000204843; -. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 139589; Distal hereditary motor neuropathy type 7. DR Orphanet; 178509; Perry syndrome. DR VEuPathDB; HostDB:ENSG00000204843; -. DR eggNOG; KOG0971; Eukaryota. DR GeneTree; ENSGT00940000155378; -. DR HOGENOM; CLU_002523_0_0_1; -. DR InParanoid; Q14203; -. DR OMA; LFEMEPV; -. DR OrthoDB; 2130750at2759; -. DR PAN-GO; Q14203; 11 GO annotations based on evolutionary models. DR PhylomeDB; Q14203; -. DR PathwayCommons; Q14203; -. DR Reactome; R-HSA-2132295; MHC class II antigen presentation. DR Reactome; R-HSA-2565942; Regulation of PLK1 Activity at G2/M Transition. [Q14203-2] DR Reactome; R-HSA-3371497; HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand. DR Reactome; R-HSA-380259; Loss of Nlp from mitotic centrosomes. [Q14203-2] DR Reactome; R-HSA-380270; Recruitment of mitotic centrosome proteins and complexes. [Q14203-2] DR Reactome; R-HSA-380284; Loss of proteins required for interphase microtubule organization from the centrosome. [Q14203-2] DR Reactome; R-HSA-380320; Recruitment of NuMA to mitotic centrosomes. [Q14203-2] DR Reactome; R-HSA-381038; XBP1(S) activates chaperone genes. DR Reactome; R-HSA-5620912; Anchoring of the basal body to the plasma membrane. [Q14203-2] DR Reactome; R-HSA-6807878; COPI-mediated anterograde transport. DR Reactome; R-HSA-6811436; COPI-independent Golgi-to-ER retrograde traffic. DR Reactome; R-HSA-8854518; AURKA Activation by TPX2. [Q14203-2] DR Reactome; R-HSA-9725370; Signaling by ALK fusions and activated point mutants. DR SignaLink; Q14203; -. DR SIGNOR; Q14203; -. DR Agora; ENSG00000204843; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 1639; 273 hits in 1160 CRISPR screens. DR CD-CODE; 8C2F96ED; Centrosome. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; DCTN1; human. DR EvolutionaryTrace; Q14203; -. DR GeneWiki; DCTN1; -. DR GenomeRNAi; 1639; -. DR Pharos; Q14203; Tbio. DR PRO; PR:Q14203; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q14203; protein. DR Bgee; ENSG00000204843; Expressed in right frontal lobe and 192 other cell types or tissues. DR ExpressionAtlas; Q14203; baseline and differential. DR GO; GO:0001669; C:acrosomal vesicle; IDA:HPA. DR GO; GO:0030424; C:axon; IBA:GO_Central. DR GO; GO:0005938; C:cell cortex; IDA:UniProtKB. DR GO; GO:0099738; C:cell cortex region; IDA:UniProtKB. DR GO; GO:0031252; C:cell leading edge; IEA:Ensembl. DR GO; GO:0120103; C:centriolar subdistal appendage; IDA:GO_Central. DR GO; GO:0005814; C:centriole; IDA:UniProtKB. DR GO; GO:0005813; C:centrosome; IDA:UniProtKB. DR GO; GO:0036064; C:ciliary basal body; IDA:HPA. DR GO; GO:0005929; C:cilium; IDA:HPA. DR GO; GO:0005737; C:cytoplasm; IDA:ARUK-UCL. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0030286; C:dynein complex; IEA:UniProtKB-KW. DR GO; GO:0045171; C:intercellular bridge; IDA:HPA. DR GO; GO:0000776; C:kinetochore; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005874; C:microtubule; IDA:UniProtKB. DR GO; GO:0005875; C:microtubule associated complex; IMP:ARUK-UCL. DR GO; GO:0015630; C:microtubule cytoskeleton; IDA:HPA. DR GO; GO:0035371; C:microtubule plus-end; IDA:UniProtKB. DR GO; GO:0072686; C:mitotic spindle; IDA:HPA. DR GO; GO:0043005; C:neuron projection; IDA:ARUK-UCL. DR GO; GO:0043025; C:neuronal cell body; IDA:ARUK-UCL. DR GO; GO:0005635; C:nuclear envelope; IDA:UniProtKB. DR GO; GO:0033011; C:perinuclear theca; IDA:HPA. DR GO; GO:0005819; C:spindle; IDA:UniProtKB. DR GO; GO:0000922; C:spindle pole; IDA:UniProtKB. DR GO; GO:0008017; F:microtubule binding; IDA:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; IPI:ARUK-UCL. DR GO; GO:0048156; F:tau protein binding; NAS:ARUK-UCL. DR GO; GO:0015631; F:tubulin binding; IDA:UniProtKB. DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW. DR GO; GO:0010457; P:centriole-centriole cohesion; IMP:UniProtKB. DR GO; GO:0000132; P:establishment of mitotic spindle orientation; IMP:UniProtKB. DR GO; GO:0099558; P:maintenance of synapse structure; TAS:ARUK-UCL. DR GO; GO:0032402; P:melanosome transport; IEA:Ensembl. DR GO; GO:0034454; P:microtubule anchoring at centrosome; IMP:UniProtKB. DR GO; GO:0000278; P:mitotic cell cycle; NAS:ProtInc. DR GO; GO:0007077; P:mitotic nuclear membrane disassembly; IMP:UniProtKB. DR GO; GO:0061744; P:motor behavior; IMP:ARUK-UCL. DR GO; GO:0007399; P:nervous system development; NAS:UniProtKB. DR GO; GO:0007528; P:neuromuscular junction development; IMP:ARUK-UCL. DR GO; GO:0050905; P:neuromuscular process; IMP:ARUK-UCL. DR GO; GO:0070050; P:neuron cellular homeostasis; IMP:ARUK-UCL. DR GO; GO:1990535; P:neuron projection maintenance; IMP:ARUK-UCL. DR GO; GO:1905515; P:non-motile cilium assembly; IMP:UniProtKB. DR GO; GO:0007097; P:nuclear migration; IBA:GO_Central. DR GO; GO:0090063; P:positive regulation of microtubule nucleation; IDA:UniProtKB. DR GO; GO:0031116; P:positive regulation of microtubule polymerization; IDA:UniProtKB. DR GO; GO:1904398; P:positive regulation of neuromuscular junction development; IMP:ARUK-UCL. DR GO; GO:0060236; P:regulation of mitotic spindle organization; IMP:UniProtKB. DR GO; GO:0042147; P:retrograde transport, endosome to Golgi; IMP:UniProtKB. DR GO; GO:0021517; P:ventral spinal cord development; IMP:ARUK-UCL. DR FunFam; 2.30.30.190:FF:000003; dynactin subunit 1 isoform X1; 1. DR Gene3D; 1.10.287.1490; -; 1. DR Gene3D; 2.30.30.190; CAP Gly-rich-like domain; 1. DR InterPro; IPR036859; CAP-Gly_dom_sf. DR InterPro; IPR000938; CAP-Gly_domain. DR InterPro; IPR022157; Dynactin. DR PANTHER; PTHR18916; DYNACTIN 1-RELATED MICROTUBULE-BINDING; 1. DR PANTHER; PTHR18916:SF6; DYNACTIN SUBUNIT 1; 1. DR Pfam; PF01302; CAP_GLY; 1. DR Pfam; PF12455; Dynactin; 1. DR SMART; SM01052; CAP_GLY; 1. DR SUPFAM; SSF74924; Cap-Gly domain; 1. DR PROSITE; PS00845; CAP_GLY_1; 1. DR PROSITE; PS50245; CAP_GLY_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Amyotrophic lateral sclerosis; KW Cell cycle; Cell division; Coiled coil; Cytoplasm; Cytoskeleton; Dynein; KW Microtubule; Mitosis; Neurodegeneration; Neuropathy; Nucleus; Parkinsonism; KW Phosphoprotein; Proteomics identification; Reference proteome; Transport; KW Ubl conjugation. FT CHAIN 1..1278 FT /note="Dynactin subunit 1" FT /id="PRO_0000083518" FT DOMAIN 48..90 FT /note="CAP-Gly" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00045" FT REGION 1..25 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 100..223 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 911..1278 FT /note="Interaction with HPS6" FT /evidence="ECO:0000269|PubMed:25189619" FT COILED 213..547 FT /evidence="ECO:0000255" FT COILED 943..1049 FT /evidence="ECO:0000255" FT COILED 1182..1211 FT /evidence="ECO:0000255" FT COMPBIAS 102..114 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 129..152 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 161..184 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 214..223 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 108 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 145 FT /note="Phosphothreonine; by SLK" FT /evidence="ECO:0000269|PubMed:23985322" FT MOD_RES 146 FT /note="Phosphothreonine; by SLK" FT /evidence="ECO:0000269|PubMed:23985322" FT MOD_RES 147 FT /note="Phosphothreonine; by SLK" FT /evidence="ECO:0000269|PubMed:23985322" FT MOD_RES 179 FT /note="Phosphoserine; by PLK1" FT /evidence="ECO:0000269|PubMed:20679239" FT MOD_RES 212 FT /note="Phosphoserine; by CDK1" FT /evidence="ECO:0000269|PubMed:20679239" FT VAR_SEQ 1..138 FT /note="MAQSKRHVYSRTPSGSRMSAEASARPLRVGSRVEVIGKGHRGTVAYVGATLF FT ATGKWVGVILDEAKGKNDGTVQGRKYFTCDEGHGIFVRQSQIQVFEDGADTTSPETPDS FT SASKVLKREGTDTTAKTSKLRGLKPKK -> MMRQ (in isoform p135 and FT isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_000760" FT VAR_SEQ 1..17 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_045392" FT VAR_SEQ 132..151 FT /note="Missing (in isoform 3 and isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_045393" FT VAR_SEQ 132..138 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000303|PubMed:8856662" FT /id="VSP_047174" FT VAR_SEQ 1066..1070 FT /note="Missing (in isoform 3, isoform 4 and isoform 5)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334" FT /id="VSP_045394" FT VARIANT 52 FT /note="F -> L (in PERRYS; mutation carriers either do not FT develop depression or they do develop it late in the FT disease course; dbSNP:rs886039227)" FT /evidence="ECO:0000269|PubMed:24676999" FT /id="VAR_071452" FT VARIANT 59 FT /note="G -> S (in HMND14; reduced affinity for microtubules FT which has been suggested to impair axonal transport; the FT effect is identical to that of complete loss of the CAP-Gly FT domain; decreased interaction with MAPRE1; no effect on its FT interaction with TBCB; dbSNP:rs121909342)" FT /evidence="ECO:0000269|PubMed:12627231, FT ECO:0000269|PubMed:16505168, ECO:0000269|PubMed:19136952, FT ECO:0000269|PubMed:19279216, ECO:0000269|PubMed:22777741" FT /id="VAR_015850" FT VARIANT 71 FT /note="G -> A (in PERRYS; dbSNP:rs67586389)" FT /evidence="ECO:0000269|PubMed:19136952" FT /id="VAR_063867" FT VARIANT 71 FT /note="G -> E (in PERRYS; dbSNP:rs67586389)" FT /evidence="ECO:0000269|PubMed:19136952" FT /id="VAR_063868" FT VARIANT 71 FT /note="G -> R (in PERRYS; reduced microtubule binding; FT results in the accumulation of intracytoplasmic inclusions; FT loss of interaction with CLIP1; significant decrease in FT motility of dynein-dynactin complex along microtubules; FT dbSNP:rs72466485)" FT /evidence="ECO:0000269|PubMed:19136952, FT ECO:0000269|PubMed:24881494, ECO:0000269|PubMed:25185702, FT ECO:0000269|PubMed:26972003" FT /id="VAR_063869" FT VARIANT 72 FT /note="T -> P (in PERRYS; dbSNP:rs72466486)" FT /evidence="ECO:0000269|PubMed:19136952" FT /id="VAR_063870" FT VARIANT 74 FT /note="Q -> P (in PERRYS; diminishes microtubule binding FT and lead to intracytoplasmic inclusions; significant FT decrease in motility of dynein-dynactin complex along FT microtubules; defective in inhibiting microtubule FT catastrophe in neurons; dbSNP:rs72466487)" FT /evidence="ECO:0000269|PubMed:19136952, FT ECO:0000269|PubMed:23874158, ECO:0000269|PubMed:25185702" FT /id="VAR_063871" FT VARIANT 78 FT /note="Y -> C (in PERRYS; significantly reduced microtubule FT binding; dbSNP:rs886039229)" FT /evidence="ECO:0000269|PubMed:24881494" FT /id="VAR_071453" FT VARIANT 163 FT /note="A -> P" FT /id="VAR_001373" FT VARIANT 196 FT /note="I -> V (no effect of its interaction with TBCB; no FT loss of localization to microtubules; dbSNP:rs55862001)" FT /evidence="ECO:0000269|PubMed:17824900, FT ECO:0000269|PubMed:22777741" FT /id="VAR_076920" FT VARIANT 287 FT /note="L -> M (in dbSNP:rs13420401)" FT /id="VAR_048677" FT VARIANT 495 FT /note="R -> Q (in dbSNP:rs17721059)" FT /evidence="ECO:0000269|PubMed:17824900" FT /id="VAR_048678" FT VARIANT 571 FT /note="M -> T (in ALS; associated with disease FT susceptibility; dbSNP:rs121909343)" FT /evidence="ECO:0000269|PubMed:15326253" FT /id="VAR_063872" FT VARIANT 670 FT /note="Y -> F (found in a patient with hereditary motor and FT sensory neuropathy; uncertain significance; FT dbSNP:rs765819985)" FT /evidence="ECO:0000269|PubMed:24627108" FT /id="VAR_073287" FT VARIANT 785 FT /note="R -> W (in ALS; associated with disease FT susceptibility; dbSNP:rs121909344)" FT /evidence="ECO:0000269|PubMed:15326253" FT /id="VAR_063873" FT VARIANT 1101 FT /note="R -> K (in ALS; associated with disease FT susceptibility; dbSNP:rs121909345)" FT /evidence="ECO:0000269|PubMed:16240349" FT /id="VAR_063874" FT VARIANT 1249 FT /note="T -> I (in ALS; uncertain significance; FT dbSNP:rs72466496)" FT /evidence="ECO:0000269|PubMed:15326253, FT ECO:0000269|PubMed:17824900, ECO:0000269|PubMed:19506225" FT /id="VAR_063875" FT MUTAGEN 68 FT /note="K->A: Abolishes interaction with CLIP1." FT /evidence="ECO:0000269|PubMed:17828275" FT MUTAGEN 90 FT /note="R->E: Abolishes interaction with CLIP1." FT /evidence="ECO:0000269|PubMed:17828275" FT MUTAGEN 145 FT /note="T->A: Affects centrosomal localization; when FT associated with A-146 and A-147." FT /evidence="ECO:0000269|PubMed:23985322" FT MUTAGEN 146 FT /note="T->A: Affects centrosomal localization; when FT associated with A-145 and A-147." FT /evidence="ECO:0000269|PubMed:23985322" FT MUTAGEN 147 FT /note="T->A: Affects centrosomal localization; when FT associated with A-145 and A-146." FT /evidence="ECO:0000269|PubMed:23985322" FT MUTAGEN 179 FT /note="S->A: Non-phosphorylatable by PLK1. Decreased FT nuclear envelope localization. No loss of microtubule- FT binding. No effect on its interaction with CLIP1." FT /evidence="ECO:0000269|PubMed:20679239" FT MUTAGEN 179 FT /note="S->D: No loss of localization to nuclear envelope. FT Decrease in microtubule-binding. No effect on its FT interaction with CLIP1." FT /evidence="ECO:0000269|PubMed:20679239" FT MUTAGEN 212 FT /note="S->A: No effect on its interaction with CLIP1 and FT PLK1." FT /evidence="ECO:0000269|PubMed:20679239" FT CONFLICT 10 FT /note="S -> N (in Ref. 7; CAA67333)" FT /evidence="ECO:0000305" FT CONFLICT 257 FT /note="Q -> R (in Ref. 2; BAG59757)" FT /evidence="ECO:0000305" FT CONFLICT 349 FT /note="K -> R (in Ref. 2; AK314352)" FT /evidence="ECO:0000305" FT CONFLICT 368 FT /note="A -> V (in Ref. 2; AK314352)" FT /evidence="ECO:0000305" FT CONFLICT 526 FT /note="H -> N (in Ref. 5; AAH71583)" FT /evidence="ECO:0000305" FT CONFLICT 618 FT /note="K -> R (in Ref. 5; AAH71583)" FT /evidence="ECO:0000305" FT CONFLICT 712 FT /note="D -> V (in Ref. 7; CAA67333)" FT /evidence="ECO:0000305" FT CONFLICT 1081 FT /note="V -> M (in Ref. 9; AAP35404)" FT /evidence="ECO:0000305" FT CONFLICT 1261 FT /note="R -> Q (in Ref. 2; BAG59757)" FT /evidence="ECO:0000305" FT CONFLICT 1274 FT /note="S -> I (in Ref. 5; AAH71583)" FT /evidence="ECO:0000305" FT STRAND 17..19 FT /evidence="ECO:0007829|PDB:2COY" FT STRAND 32..35 FT /evidence="ECO:0007829|PDB:1TXQ" FT TURN 36..38 FT /evidence="ECO:0007829|PDB:1TXQ" FT STRAND 41..48 FT /evidence="ECO:0007829|PDB:1TXQ" FT STRAND 51..55 FT /evidence="ECO:0007829|PDB:1TXQ" FT STRAND 57..65 FT /evidence="ECO:0007829|PDB:1TXQ" FT STRAND 67..73 FT /evidence="ECO:0007829|PDB:1TXQ" FT STRAND 76..78 FT /evidence="ECO:0007829|PDB:1TXQ" FT TURN 83..85 FT /evidence="ECO:0007829|PDB:2HQH" FT STRAND 86..89 FT /evidence="ECO:0007829|PDB:1TXQ" FT HELIX 91..93 FT /evidence="ECO:0007829|PDB:1TXQ" FT STRAND 94..96 FT /evidence="ECO:0007829|PDB:1TXQ" SQ SEQUENCE 1278 AA; 141695 MW; 6DCEA5E67856E4BC CRC64; MAQSKRHVYS RTPSGSRMSA EASARPLRVG SRVEVIGKGH RGTVAYVGAT LFATGKWVGV ILDEAKGKND GTVQGRKYFT CDEGHGIFVR QSQIQVFEDG ADTTSPETPD SSASKVLKRE GTDTTAKTSK LRGLKPKKAP TARKTTTRRP KPTRPASTGV AGASSSLGPS GSASAGELSS SEPSTPAQTP LAAPIIPTPV LTSPGAVPPL PSPSKEEEGL RAQVRDLEEK LETLRLKRAE DKAKLKELEK HKIQLEQVQE WKSKMQEQQA DLQRRLKEAR KEAKEALEAK ERYMEEMADT ADAIEMATLD KEMAEERAES LQQEVEALKE RVDELTTDLE ILKAEIEEKG SDGAASSYQL KQLEEQNARL KDALVRMRDL SSSEKQEHVK LQKLMEKKNQ ELEVVRQQRE RLQEELSQAE STIDELKEQV DAALGAEEMV EMLTDRNLNL EEKVRELRET VGDLEAMNEM NDELQENARE TELELREQLD MAGARVREAQ KRVEAAQETV ADYQQTIKKY RQLTAHLQDV NRELTNQQEA SVERQQQPPP ETFDFKIKFA ETKAHAKAIE MELRQMEVAQ ANRHMSLLTA FMPDSFLRPG GDHDCVLVLL LMPRLICKAE LIRKQAQEKF ELSENCSERP GLRGAAGEQL SFAAGLVYSL SLLQATLHRY EHALSQCSVD VYKKVGSLYP EMSAHERSLD FLIELLHKDQ LDETVNVEPL TKAIKYYQHL YSIHLAEQPE DCTMQLADHI KFTQSALDCM SVEVGRLRAF LQGGQEATDI ALLLRDLETS CSDIRQFCKK IRRRMPGTDA PGIPAALAFG PQVSDTLLDC RKHLTWVVAV LQEVAAAAAQ LIAPLAENEG LLVAALEELA FKASEQIYGT PSSSPYECLR QSCNILISTM NKLATAMQEG EYDAERPPSK PPPVELRAAA LRAEITDAEG LGLKLEDRET VIKELKKSLK IKGEELSEAN VRLSLLEKKL DSAAKDADER IEKVQTRLEE TQALLRKKEK EFEETMDALQ ADIDQLEAEK AELKQRLNSQ SKRTIEGLRG PPPSGIATLV SGIAGEEQQR GAIPGQAPGS VPGPGLVKDS PLLLQQISAM RLHISQLQHE NSILKGAQMK ASLASLPPLH VAKLSHEGPG SELPAGALYR KTSQLLETLN QLSTHTHVVD ITRTSPAAKS PSAQLMEQVA QLKSLSDTVE KLKDEVLKET VSQRPGATVP TDFATFPSSA FLRAKEEQQD DTVYMGKVTF SCAAGFGQRH RLVLTQEQLH QLHSRLIS // ID DPOG1_HUMAN Reviewed; 1239 AA. AC P54098; Q8NFM2; Q92515; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 1. DT 28-JAN-2026, entry version 236. DE RecName: Full=DNA polymerase subunit gamma-1; DE EC=2.7.7.7 {ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:19837034, ECO:0000269|PubMed:9558343}; DE AltName: Full=3'-5' exodeoxyribonuclease; DE EC=3.1.11.- {ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:26095671, ECO:0000269|PubMed:9558343}; DE AltName: Full=5'-deoxyribose-phosphate lyase; DE EC=4.2.99.- {ECO:0000269|PubMed:9770471}; DE AltName: Full=Mitochondrial DNA polymerase catalytic subunit; DE AltName: Full=PolG-alpha; GN Name=POLG {ECO:0000303|PubMed:10827171, ECO:0000312|HGNC:HGNC:9179}; GN Synonyms=MDP1, POLG1 {ECO:0000303|PubMed:12707443}, POLGA; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND DOMAIN. RX PubMed=8884268; DOI=10.1006/geno.1996.0490; RA Ropp P.A., Copeland W.C.; RT "Cloning and characterization of the human mitochondrial DNA polymerase, RT DNA polymerase gamma."; RL Genomics 36:449-458(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=9034326; DOI=10.1016/s0378-1119(96)00663-4; RA Lecrenier N.L., van der Bruggen P., Foury F.; RT "Mitochondrial DNA polymerases from yeast to man: a new family of RT polymerases."; RL Gene 185:147-152(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT GLN-GLN-55 INS. RC TISSUE=Brain; RA Watanabe T.K., Shimizu F., Nishino N., Fujiwara T., Kanemoto N., Suzuki M., RA Nakamura Y., Hirai Y., Maekawa H., Takahashi E.; RL Submitted (MAR-1996) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLN-55 INS; GLN-193; RP CYS-546; LYS-662; TRP-1142; GLY-1143; CYS-1146 AND HIS-1236. RG NIEHS SNPs program; RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lymph, and Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=9558343; DOI=10.1021/bi972685u; RA Graves S.W., Johnson A.A., Johnson K.A.; RT "Expression, purification, and initial kinetic characterization of the RT large subunit of the human mitochondrial DNA polymerase."; RL Biochemistry 37:6050-6058(1998). RN [7] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=9770471; DOI=10.1073/pnas.95.21.12244; RA Longley M.J., Prasad R., Srivastava D.K., Wilson S.H., Copeland W.C.; RT "Identification of 5'-deoxyribose phosphate lyase activity in human DNA RT polymerase gamma and its role in mitochondrial base excision repair in RT vitro."; RL Proc. Natl. Acad. Sci. U.S.A. 95:12244-12248(1998). RN [8] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP ASP-198; ASP-890 AND ASP-1135. RX PubMed=10827171; DOI=10.1074/jbc.m000559200; RA Spelbrink J.N., Toivonen J.M., Hakkaart G.A., Kurkela J.M., Cooper H.M., RA Lehtinen S.K., Lecrenier N., Back J.W., Speijer D., Foury F., Jacobs H.T.; RT "In vivo functional analysis of the human mitochondrial DNA polymerase POLG RT expressed in cultured human cells."; RL J. Biol. Chem. 275:24818-24828(2000). RN [9] RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, AND MUTAGENESIS OF GLU-200. RX PubMed=11477093; DOI=10.1074/jbc.m106045200; RA Johnson A.A., Johnson K.A.; RT "Fidelity of nucleotide incorporation by human mitochondrial DNA RT polymerase."; RL J. Biol. Chem. 276:38090-38096(2001). RN [10] RP FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT. RX PubMed=11477094; DOI=10.1074/jbc.m106046200; RA Johnson A.A., Johnson K.A.; RT "Exonuclease proofreading by human mitochondrial DNA polymerase."; RL J. Biol. Chem. 276:38097-38107(2001). RN [11] RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND SUBUNIT. RX PubMed=11504725; DOI=10.1074/jbc.m105230200; RA Longley M.J., Nguyen D., Kunkel T.A., Copeland W.C.; RT "The fidelity of human DNA polymerase gamma with and without exonucleolytic RT proofreading and the p55 accessory subunit."; RL J. Biol. Chem. 276:38555-38562(2001). RN [12] RP REVIEW, AND DOMAIN. RX PubMed=15189144; DOI=10.1146/annurev.biochem.72.121801.161455; RA Kaguni L.S.; RT "DNA polymerase gamma, the mitochondrial replicase."; RL Annu. Rev. Biochem. 73:293-320(2004). RN [13] RP FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT. RX PubMed=15167897; DOI=10.1038/sj.emboj.7600257; RA Korhonen J.A., Pham X.H., Pellegrini M., Falkenberg M.; RT "Reconstitution of a minimal mtDNA replisome in vitro."; RL EMBO J. 23:2423-2429(2004). RN [14] RP SUBCELLULAR LOCATION, ASSOCIATION WITH MITOCHONDRIAL DNA, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=18063578; DOI=10.1074/jbc.m708444200; RA Bogenhagen D.F., Rousseau D., Burke S.; RT "The layered structure of human mitochondrial DNA nucleoids."; RL J. Biol. Chem. 283:3665-3675(2008). RN [15] RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF ASP-274, CHARACTERIZATION OF RP VARIANT LS HIS-232, CHARACTERIZATION OF VARIANTS PEOB1 ALA-268 AND ARG-304, RP AND CHARACTERIZATION OF VARIANTS GLN-275; LEU-277; ARG-303 AND ARG-305. RX PubMed=26095671; DOI=10.1038/ncomms8303; RA Macao B., Uhler J.P., Siibak T., Zhu X., Shi Y., Sheng W., Olsson M., RA Stewart J.B., Gustafsson C.M., Falkenberg M.; RT "The exonuclease activity of DNA polymerase gamma is required for ligation RT during mitochondrial DNA replication."; RL Nat. Commun. 6:7303-7303(2015). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [17] RP INTERACTION WITH TTC3. RX PubMed=29290964; DOI=10.18632/oncotarget.22476; RA Gong Y., Wang X., Shang X., Xiao S.P., Li W., Shang Y., Dou F.; RT "Tetratricopeptide repeat domain 3 overexpression tends to form aggregates RT and inhibit ubiquitination and degradation of DNA polymerase gamma."; RL Oncotarget 8:106475-106485(2017). RN [18] RP INTERACTION WITH LIG3. RX PubMed=33855352; DOI=10.1093/brain/awab056; RA Bonora E., Chakrabarty S., Kellaris G., Tsutsumi M., Bianco F., RA Bergamini C., Ullah F., Isidori F., Liparulo I., Diquigiovanni C., RA Masin L., Rizzardi N., Cratere M.G., Boschetti E., Papa V., Maresca A., RA Cenacchi G., Casadio R., Martelli P., Matera I., Ceccherini I., Fato R., RA Raiola G., Arrigo S., Signa S., Sementa A.R., Severino M., Striano P., RA Fiorillo C., Goto T., Uchino S., Oyazato Y., Nakamura H., Mishra S.K., RA Yeh Y.S., Kato T., Nozu K., Tanboon J., Morioka I., Nishino I., Toda T., RA Goto Y.I., Ohtake A., Kosaki K., Yamaguchi Y., Nonaka I., Iijima K., RA Mimaki M., Kurahashi H., Raams A., MacInnes A., Alders M., Engelen M., RA Linthorst G., de Koning T., den Dunnen W., Dijkstra G., van Spaendonck K., RA van Gent D.C., Aronica E.M., Picco P., Carelli V., Seri M., Katsanis N., RA Duijkers F.A.M., Taniguchi-Ikeda M., De Giorgio R.; RT "Biallelic variants in LIG3 cause a novel mitochondrial RT neurogastrointestinal encephalomyopathy."; RL Brain 144:1451-1466(2021). RN [19] RP X-RAY CRYSTALLOGRAPHY (3.24 ANGSTROMS) OF 70-1239, FUNCTION, CATALYTIC RP ACTIVITY, SUBUNIT, AND MUTAGENESIS OF 543-VAL--LEU-558; LEU-549; LEU-552 RP AND LYS-553. RX PubMed=19837034; DOI=10.1016/j.cell.2009.07.050; RA Lee Y.S., Kennedy W.D., Yin Y.W.; RT "Structural insight into processive human mitochondrial DNA synthesis and RT disease-related polymerase mutations."; RL Cell 139:312-324(2009). RN [20] RP X-RAY CRYSTALLOGRAPHY (3.30 ANGSTROMS) OF 30-1239 IN COMPLEX WITH MG(2+); RP PRIMER-TEMPLATE; 2',3'-DIDEOXYCYTIDINE 5'-TRIPHOSPHATE AND INHIBITOR RP ZALCITABINE, COFACTOR, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, RP SUBUNIT, MUTAGENESIS OF LYS-498; LYS-499 AND LYS-501, AND DOMAIN. RX PubMed=26056153; DOI=10.15252/embj.201591520; RA Szymanski M.R., Kuznetsov V.B., Shumate C., Meng Q., Lee Y.S., Patel G., RA Patel S., Yin Y.W.; RT "Structural basis for processivity and antiviral drug toxicity in human RT mitochondrial DNA replicase."; RL EMBO J. 34:1959-1970(2015). RN [21] RP STRUCTURE BY ELECTRON MICROSCOPY (2.46 ANGSTROMS) IN COMPLEX WITH RP 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, RP ACTIVE SITE, SITE, AND MUTAGENESIS OF ASP-198; GLU-200 AND ARG-853. RX PubMed=37202477; DOI=10.1038/s41594-023-00980-2; RA Park J., Herrmann G.K., Mitchell P.G., Sherman M.B., Yin Y.W.; RT "Polgamma coordinates DNA synthesis and proofreading to ensure RT mitochondrial genome integrity."; RL Nat. Struct. Mol. Biol. 30:812-823(2023). RN [22] RP VARIANTS PEOB1 PRO-3; ARG-304; THR-467 AND CYS-955. RX PubMed=11431686; DOI=10.1038/90034; RA Van Goethem G., Dermaut B., Loefgren A., Martin J.-J., Van Broeckhoven C.; RT "Mutation of POLG is associated with progressive external ophthalmoplegia RT characterized by mtDNA deletions."; RL Nat. Genet. 28:211-212(2001). RN [23] RP VARIANTS PEOA1 ASP-923; HIS-943; CYS-955; SER-957 AND LEU-1176, AND RP VARIANTS PEOB1 ILE-251; LEU-309 AND SER-848. RX PubMed=12210792; DOI=10.1002/ana.10278; RA Lamantea E., Tiranti V., Bordoni A., Toscano A., Bono F., Servidei S., RA Papadimitriou A., Spelbrink H., Silvestri L., Casari G., Comi G.P., RA Zeviani M.; RT "Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of RT autosomal dominant or recessive progressive external ophthalmoplegia."; RL Ann. Neurol. 52:211-219(2002). RN [24] RP CHARACTERIZATION OF VARIANT PEOA1 CYS-955, FUNCTION, AND CATALYTIC RP ACTIVITY. RX PubMed=11897778; DOI=10.1074/jbc.c200100200; RA Ponamarev M.V., Longley M.J., Nguyen D., Kunkel T.A., Copeland W.C.; RT "Active site mutation in DNA polymerase gamma associated with progressive RT external ophthalmoplegia causes error-prone DNA synthesis."; RL J. Biol. Chem. 277:15225-15228(2002). RN [25] RP VARIANTS PEOB1 TRP-579; LEU-587; THR-889 AND VAL-1076, AND VARIANT RP HIS-1236. RX PubMed=12975295; DOI=10.1001/archneur.60.9.1279; RA Filosto M., Mancuso M., Nishigaki Y., Pancrudo J., Harati Y., Gooch C., RA Mankodi A., Bayne L., Bonilla E., Shanske S., Hirano M., DiMauro S.; RT "Clinical and genetic heterogeneity in progressive external ophthalmoplegia RT due to mutations in polymerase gamma."; RL Arch. Neurol. 60:1279-1284(2003). RN [26] RP VARIANTS MTDPS4B ILE-251; LEU-587 AND SER-864. RX PubMed=12825077; DOI=10.1038/sj.ejhg.5201002; RA Van Goethem G., Schwartz M., Loefgren A., Dermaut B., Van Broeckhoven C., RA Vissing J.; RT "Novel POLG mutations in progressive external ophthalmoplegia mimicking RT mitochondrial neurogastrointestinal encephalomyopathy."; RL Eur. J. Hum. Genet. 11:547-549(2003). RN [27] RP VARIANT PEOB1 SER-848. RX PubMed=12872260; DOI=10.1002/humu.10246; RA Van Goethem G., Loefgren A., Dermaut B., Ceuterick C., Martin J.-J., RA Van Broeckhoven C.; RT "Digenic progressive external ophthalmoplegia in a sporadic patient: RT recessive mutations in POLG and C10orf2/Twinkle."; RL Hum. Mutat. 22:175-176(2003). RN [28] RP VARIANTS PEOB1 ILE-251; ALA-268; ARG-312; THR-467; GLN-562; LEU-587; RP PRO-807 AND TYR-932, AND VARIANTS GLY-1143 AND HIS-1236. RX PubMed=14635118; DOI=10.1002/humu.9203; RA Di Fonzo A., Bordoni A., Crimi M., Sara G., Del Bo R., Bresolin N., RA Comi G.P.; RT "POLG mutations in sporadic mitochondrial disorders with multiple mtDNA RT deletions."; RL Hum. Mutat. 22:498-499(2003). RN [29] RP VARIANTS PEOB1 TRP-227; ILE-251; ARG-312; VAL-431; THR-467; GLN-1047; RP CYS-1096 AND CYS-1104. RX PubMed=12707443; DOI=10.1212/01.wnl.0000056088.09408.3c; RA Agostino A., Valletta L., Chinnery P.F., Ferrari G., Carrara F., RA Taylor R.W., Schaefer A.M., Turnbull D.M., Tiranti V., Zeviani M.; RT "Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external RT ophthalmoplegia (PEO)."; RL Neurology 60:1354-1356(2003). RN [30] RP VARIANT SCAE THR-467. RX PubMed=14694057; DOI=10.1212/01.wnl.0000098997.23471.65; RA Van Goethem G., Mercelis R., Loefgren A., Seneca S., Ceuterick C., RA Martin J.-J., Van Broeckhoven C.; RT "Patient homozygous for a recessive POLG mutation presents with features of RT MERRF."; RL Neurology 61:1811-1813(2003). RN [31] RP VARIANTS SANDO PRO-3; ARG-304; THR-467; TRP-627 AND CYS-955. RX PubMed=12565911; DOI=10.1016/s0960-8966(02)00216-x; RA Van Goethem G., Martin J.-J., Dermaut B., Loefgren A., Wibail A., RA Ververken D., Tack P., Dehaene I., Van Zandijcke M., Moonen M., RA Ceuterick C., De Jonghe P., Van Broeckhoven C.; RT "Recessive POLG mutations presenting with sensory and ataxic neuropathy in RT compound heterozygote patients with progressive external ophthalmoplegia."; RL Neuromuscul. Disord. 13:133-142(2003). RN [32] RP VARIANT MTDPS4A THR-467. RX PubMed=15122711; DOI=10.1002/ana.20079; RA Naviaux R.K., Nguyen K.V.; RT "POLG mutations associated with Alpers' syndrome and mitochondrial DNA RT depletion."; RL Ann. Neurol. 55:706-712(2004). RN [33] RP VARIANTS PEOB1 TRP-227; ILE-251; LEU-309; LEU-587; SER-848; ILE-1106 AND RP LEU-1176. RX PubMed=15349879; DOI=10.1002/ana.20219; RA Lamantea E., Zeviani M.; RT "Sequence analysis of familial PEO shows additional mutations associated RT with the 752C-->T and 3527C-->T changes in the POLG1 gene."; RL Ann. Neurol. 56:454-455(2004). RN [34] RP VARIANT PEOA1 CYS-831. RX PubMed=15534189; DOI=10.1001/archneur.61.11.1777; RA Mancuso M., Filosto M., Oh S.J., DiMauro S.; RT "A novel polymerase gamma mutation in a family with ophthalmoplegia, RT neuropathy, and parkinsonism."; RL Arch. Neurol. 61:1777-1779(2004). RN [35] RP VARIANTS PEOA1 CYS-953 AND CYS-955, AND VARIANTS PEOB1 ASP-468 AND RP THR-1105. RX PubMed=15351195; DOI=10.1016/s0140-6736(04)16983-3; RA Luoma P., Melberg A., Rinne J.O., Kaukonen J.A., Nupponen N.N., RA Chalmers R.M., Oldfors A., Rautakorpi I., Peltonen L., Majamaa K., RA Somer H., Suomalainen A.; RT "Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma RT mutations: clinical and molecular genetic study."; RL Lancet 364:875-882(2004). RN [36] RP VARIANTS SANDO TYR-932 AND ARG-1051. RX PubMed=14745080; DOI=10.1212/wnl.62.2.316; RA Mancuso M., Filosto M., Bellan M., Liguori R., Montagna P., Baruzzi A., RA DiMauro S., Carelli V.; RT "POLG mutations causing ophthalmoplegia, sensorimotor polyneuropathy, RT ataxia, and deafness."; RL Neurology 62:316-318(2004). RN [37] RP VARIANT PEOB1 THR-467, VARIANT SANDO SER-748, AND VARIANT GLY-1143. RX PubMed=15477547; DOI=10.1212/01.wnl.0000140494.58732.83; RA Van Goethem G., Luoma P., Rantamaeki M., Al-Memar A., Kaakkola S., RA Hackman P., Krahe R., Loefgren A., Martin J.-J., De Jonghe P., RA Suomalainen A., Udd B., Van Broeckhoven C.; RT "POLG mutations in neurodegenerative disorders with ataxia but no muscle RT involvement."; RL Neurology 63:1251-1257(2004). RN [38] RP VARIANT SANDO SER-748, AND VARIANT GLY-1143. RX PubMed=16080118; DOI=10.1086/444548; RA Hakonen A.H., Heiskanen S., Juvonen V., Lappalainen I., Luoma P.T., RA Rantamaeki M., Van Goethem G., Loefgren A., Hackman P., Paetau A., RA Kaakkola S., Majamaa K., Varilo T., Udd B., Kaeaeriaeinen H., Bindoff L.A., RA Suomalainen A.; RT "Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal RT recessive ataxia with ancient European origin."; RL Am. J. Hum. Genet. 77:430-441(2005). RN [39] RP VARIANTS MTDPS4A SER-748 AND SER-848. RX PubMed=15929042; DOI=10.1002/ana.20498; RA Davidzon G., Mancuso M., Ferraris S., Quinzii C., Hirano M., Peters H.L., RA Kirby D., Thorburn D.R., DiMauro S.; RT "POLG mutations and Alpers syndrome."; RL Ann. Neurol. 57:921-923(2005). RN [40] RP VARIANTS MTDPS4A GLY-232; PRO-244; ILE-251; THR-467; LEU-587; SER-748; RP SER-848 AND PRO-957, AND VARIANT GLY-1143. RX PubMed=15689359; DOI=10.1093/brain/awh410; RA Ferrari G., Lamantea E., Donati A., Filosto M., Briem E., Carrara F., RA Parini R., Simonati A., Santer R., Zeviani M.; RT "Infantile hepatocerebral syndromes associated with mutations in the RT mitochondrial DNA polymerase-gammaA."; RL Brain 128:723-731(2005). RN [41] RP VARIANT PEOB1 THR-467, VARIANT SANDO GLN-627, VARIANT HIS-1236, RP CHARACTERIZATION OF VARIANT PEOB1 THR-467, CHARACTERIZATION OF VARIANT RP SANDO GLN-627, FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=15917273; DOI=10.1093/hmg/ddi196; RA Luoma P.T., Luo N., Loescher W.N., Farr C.L., Horvath R., Wanschitz J., RA Kiechl S., Kaguni L.S., Suomalainen A.; RT "Functional defects due to spacer-region mutations of human mitochondrial RT DNA polymerase in a family with an ataxia-myopathy syndrome."; RL Hum. Mol. Genet. 14:1907-1920(2005). RN [42] RP VARIANTS SANDO THR-467; HIS-497 AND SER-748. RX PubMed=15824347; DOI=10.1212/01.wnl.0000156516.77696.5a; RA Winterthun S., Ferrari G., He L., Taylor R.W., Zeviani M., Turnbull D.M., RA Engelsen B.A., Moen G., Bindoff L.A.; RT "Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial RT polymerase gamma mutations."; RL Neurology 64:1204-1208(2005). RN [43] RP VARIANTS PEOB1 ARG-737 AND TRP-853. RX PubMed=16634032; DOI=10.1002/ana.20831; RA Davidzon G., Greene P., Mancuso M., Klos K.J., Ahlskog J.E., Hirano M., RA DiMauro S.; RT "Early-onset familial parkinsonism due to POLG mutations."; RL Ann. Neurol. 59:859-862(2006). RN [44] RP VARIANTS PEOB1 LEU-603; TRP-853; CYS-1146 AND ASN-1184. RX PubMed=16401742; DOI=10.1001/archneur.63.1.107; RA Gonzalez-Vioque E., Blazquez A., Fernandez-Moreira D., Bornstein B., RA Bautista J., Arpa J., Navarro C., Campos Y., Fernandez-Moreno M.A., RA Garesse R., Arenas J., Martin M.A.; RT "Association of novel POLG mutations and multiple mitochondrial DNA RT deletions with variable clinical phenotypes in a Spanish population."; RL Arch. Neurol. 63:107-111(2006). RN [45] RP VARIANTS PEOB1 HIS-308; TRP-574 AND ARG-648, VARIANT SANDO VAL-517, AND RP VARIANTS MTDPS4A ASP-767; HIS-879; SER-885; PRO-914; HIS-1096 AND ASN-1191. RX PubMed=16621917; DOI=10.1093/brain/awl088; RA Horvath R., Hudson G., Ferrari G., Fuetterer N., Ahola S., Lamantea E., RA Prokisch H., Lochmueller H., McFarland R., Ramesh V., Klopstock T., RA Freisinger P., Salvi F., Mayr J.A., Santer R., Tesarova M., Zeman J., RA Udd B., Taylor R.W., Turnbull D., Hanna M., Fialho D., Suomalainen A., RA Zeviani M., Chinnery P.F.; RT "Phenotypic spectrum associated with mutations of the mitochondrial RT polymerase gamma gene."; RL Brain 129:1674-1684(2006). RN [46] RP VARIANTS PEOB1 ARG-304; ASP-380 AND THR-467, VARIANT SANDO SER-748, VARIANT RP MTDPS4A PRO-914, AND VARIANTS GLY-1143 AND HIS-1236. RX PubMed=16639411; DOI=10.1038/sj.ejhg.5201627; RA Naiemi M., Bannwarth S., Procaccio V., Pouget J., Desnuelle C., RA Pellissier J.-F., Roetig A., Munnich A., Calvas P., Richelme C., RA Jonveaux P., Castelnovo G., Simon M., Clanet M., Wallace D., RA Paquis-Flucklinger V.; RT "Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple RT deletions or depletion of mitochondrial DNA by a dHPLC-based assay."; RL Eur. J. Hum. Genet. 14:917-922(2006). RN [47] RP ERRATUM OF PUBMED:16639411. RA Naiemi M., Bannwarth S., Procaccio V., Pouget J., Desnuelle C., RA Pellissier J.-F., Roetig A., Munnich A., Calvas P., Richelme C., RA Jonveaux P., Castelnovo G., Simon M., Clanet M., Wallace D., RA Paquis-Flucklinger V.; RL Eur. J. Hum. Genet. 15:607-607(2006). RN [48] RP VARIANTS SANDO ARG-648 AND CYS-807. RX PubMed=16919951; DOI=10.1016/j.nmd.2006.05.016; RA Gago M.F., Rosas M.J., Guimaraes J., Ferreira M., Vilarinho L., Castro L., RA Carpenter S.; RT "SANDO: two novel mutations in POLG1 gene."; RL Neuromuscul. Disord. 16:507-509(2006). RN [49] RP VARIANT PEOA1 ASN-511, AND VARIANT PHE-463. RX PubMed=17420318; DOI=10.1001/archneur.64.4.553; RA Hudson G., Schaefer A.M., Taylor R.W., Tiangyou W., Gibson A., Venables G., RA Griffiths P., Burn D.J., Turnbull D.M., Chinnery P.F.; RT "Mutation of the linker region of the polymerase gamma-1 (POLG1) gene RT associated with progressive external ophthalmoplegia and Parkinsonism."; RL Arch. Neurol. 64:553-557(2007). RN [50] RP VARIANT PEOA1 CYS-831. RX PubMed=17846414; DOI=10.1212/01.wnl.0000276955.23735.eb; RA Luoma P.T., Eerola J., Ahola S., Hakonen A.H., Hellstroem O., RA Kivistoe K.T., Tienari P.J., Suomalainen A.; RT "Mitochondrial DNA polymerase gamma variants in idiopathic sporadic RT Parkinson disease."; RL Neurology 69:1152-1159(2007). RN [51] RP VARIANT PEOA1 HIS-1186. RX PubMed=18575922; DOI=10.1007/s00415-008-0926-3; RA Virgilio R., Ronchi D., Hadjigeorgiou G.M., Bordoni A., Saladino F., RA Moggio M., Adobbati L., Kafetsouli D., Tsironi E., Previtali S., RA Papadimitriou A., Bresolin N., Comi G.P.; RT "Novel Twinkle (PEO1) gene mutations in Mendelian progressive external RT ophthalmoplegia."; RL J. Neurol. 255:1384-1391(2008). RN [52] RP VARIANTS LS HIS-232 AND SER-848, VARIANTS MTDPS4A ILE-251; THR-467; RP LEU-587; SER-748; CYS-831; SER-848; PRO-914; TYR-1110; ARG-1134 AND RP LYS-1136, AND VARIANTS GLY-1143 AND HIS-1236. RX PubMed=18828154; DOI=10.1002/humu.20852; RA Taanman J.-W., Rahman S., Pagnamenta A.T., Morris A.A.M., RA Bitner-Glindzicz M., Wolf N.I., Leonard J.V., Clayton P.T., RA Schapira A.H.V.; RT "Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA RT depletion."; RL Hum. Mutat. 30:248-254(2009). RN [53] RP VARIANTS MTDPS4B TRP-227 AND SER-848. RX PubMed=19307547; DOI=10.1212/01.wnl.0000345002.47396.e1; RA Giordano C., Powell H., Leopizzi M., de Curtis M., Travaglini C., RA Sebastiani M., Gallo P., Taylor R.W., d'Amati G.; RT "Fatal congenital myopathy and gastrointestinal pseudo-obstruction due to RT POLG1 mutations."; RL Neurology 72:1103-1105(2009). RN [54] RP VARIANTS SCAE THR-467 AND SER-748, AND VARIANTS MTDPS4A ARG-303; THR-467 RP AND SER-848. RX PubMed=20400524; DOI=10.1093/brain/awq067; RA Tzoulis C., Neckelmann G., Moerk S.J., Engelsen B.E., Viscomi C., Moen G., RA Ersland L., Zeviani M., Bindoff L.A.; RT "Localized cerebral energy failure in DNA polymerase gamma-associated RT encephalopathy syndromes."; RL Brain 133:1428-1437(2010). RN [55] RP VARIANTS PEOB1 LEU-277 AND CYS-943. RX PubMed=21301859; DOI=10.1007/s00415-011-5936-x; RA Sato K., Yabe I., Yaguchi H., Nakano F., Kunieda Y., Saitoh S., Sasaki H.; RT "Genetic analysis of two Japanese families with progressive external RT ophthalmoplegia and parkinsonism."; RL J. Neurol. 258:1327-1332(2011). RN [56] RP VARIANTS MTDPS4A ARG-305; THR-467; SER-748; SER-848; CYS-852 AND ARG-966. RX PubMed=22000311; DOI=10.1016/j.pediatrneurol.2011.07.008; RA Hunter M.F., Peters H., Salemi R., Thorburn D., Mackay M.T.; RT "Alpers syndrome with mutations in POLG: clinical and investigative RT features."; RL Pediatr. Neurol. 45:311-318(2011). RN [57] RP VARIANT MTDPS4A CYS-1096. RX PubMed=25129007; DOI=10.1007/s13312-014-0475-z; RA Bijarnia-Mahay S., Mohan N., Goyal D., Verma I.C.; RT "Mitochondrial DNA depletion syndrome causing liver failure."; RL Indian Pediatr. 51:666-668(2014). RN [58] RP INVOLVEMENT IN SCAE, AND VARIANTS SCAE THR-467; HIS-497 AND SER-748. RX PubMed=26942291; DOI=10.1016/j.ajhg.2016.01.009; RA Sandford E., Bird T.D., Li J.Z., Burmeister M.; RT "PRICKLE2 mutations might not be involved in epilepsy."; RL Am. J. Hum. Genet. 98:588-589(2016). RN [59] RP VARIANTS GLN-275 AND SER-848. RX PubMed=30552426; DOI=10.1038/s41431-018-0299-8; RA Papuc S.M., Abela L., Steindl K., Begemann A., Simmons T.L., Schmitt B., RA Zweier M., Oneda B., Socher E., Crowther L.M., Wohlrab G., Gogoll L., RA Poms M., Seiler M., Papik M., Baldinger R., Baumer A., Asadollahi R., RA Kroell-Seger J., Schmid R., Iff T., Schmitt-Mechelke T., Otten K., RA Hackenberg A., Addor M.C., Klein A., Azzarello-Burri S., Sticht H., RA Joset P., Plecko B., Rauch A.; RT "The role of recessive inheritance in early-onset epileptic RT encephalopathies: a combined whole-exome sequencing and copy number RT study."; RL Eur. J. Hum. Genet. 27:408-421(2019). CC -!- FUNCTION: Catalytic subunit of DNA polymerase gamma solely responsible CC for replication of mitochondrial DNA (mtDNA). Replicates both heavy and CC light strands of the circular mtDNA genome using a single-stranded DNA CC template, RNA primers and the four deoxyribonucleoside triphosphates as CC substrates (PubMed:11477093, PubMed:11897778, PubMed:15917273, CC PubMed:19837034, PubMed:9558343). Has 5' -> 3' polymerase activity. CC Functionally interacts with TWNK and SSBP1 at the replication fork to CC form a highly processive replisome, where TWNK unwinds the double- CC stranded DNA template prior to replication and SSBP1 covers the CC parental heavy strand to enable continuous replication of the entire CC mitochondrial genome. A single nucleotide incorporation cycle includes CC binding of the incoming nucleotide at the insertion site, a CC phosphodiester bond formation reaction that extends the 3'-end of the CC primer DNA, and translocation of the primer terminus to the post- CC insertion site. After completing replication of a mtDNA strand, CC mediates 3' -> 5' exonucleolytic degradation at the nick to enable CC proper ligation (PubMed:11477093, PubMed:11897778, PubMed:15167897, CC PubMed:15917273, PubMed:19837034, PubMed:26095671, PubMed:9558343). CC Highly accurate due to high nucleotide selectivity and 3' -> 5' CC exonucleolytic proofreading. Proficiently corrects base substitutions, CC single-base additions and deletions in non-repetitive sequences and CC short repeats, but displays lower proofreading activity when CC replicating longer homopolymeric stretches. Exerts exonuclease activity CC toward single-stranded DNA and double-stranded DNA containing 3'- CC terminal mispairs. When a misincorporation occurs, transitions from CC replication to a pro-nucleolytic editing mode and removes the CC missincorporated nucleoside in the exonuclease active site. Proceeds CC via an SN2 nucleolytic mechanism in which Asp-198 catalyzes CC phosphodiester bond hydrolysis and Glu-200 stabilizes the leaving CC group. As a result the primer strand becomes one nucleotide shorter and CC is positioned in the post-insertion site, ready to resume DNA synthesis CC (PubMed:10827171, PubMed:11477094, PubMed:11504725, PubMed:37202477). CC Exerts 5'-deoxyribose phosphate (dRP) lyase activity and mediates CC repair-associated mtDNA synthesis (gap filling) in base-excision repair CC pathway. Catalyzes the release of the 5'-terminal 2-deoxyribose-5- CC phosphate sugar moiety from incised apurinic/apyrimidinic (AP) sites to CC produce a substrate for DNA ligase. The dRP lyase reaction does not CC require divalent metal ions and likely proceeds via a Schiff base CC intermediate in a beta-elimination reaction mechanism (PubMed:9770471). CC {ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:11504725, CC ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:15167897, CC ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:19837034, CC ECO:0000269|PubMed:26095671, ECO:0000269|PubMed:37202477, CC ECO:0000269|PubMed:9558343, ECO:0000269|PubMed:9770471}. CC -!- CATALYTIC ACTIVITY: CC Reaction=DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + CC diphosphate; Xref=Rhea:RHEA:22508, Rhea:RHEA-COMP:17339, Rhea:RHEA- CC COMP:17340, ChEBI:CHEBI:33019, ChEBI:CHEBI:61560, ChEBI:CHEBI:173112; CC EC=2.7.7.7; Evidence={ECO:0000269|PubMed:10827171, CC ECO:0000269|PubMed:11477093, ECO:0000269|PubMed:11897778, CC ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:15917273, CC ECO:0000269|PubMed:19837034, ECO:0000269|PubMed:26056153, CC ECO:0000269|PubMed:26095671, ECO:0000269|PubMed:37202477, CC ECO:0000269|PubMed:9558343}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22509; CC Evidence={ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:15167897, CC ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:19837034, CC ECO:0000269|PubMed:26056153, ECO:0000269|PubMed:26095671, CC ECO:0000269|PubMed:37202477, ECO:0000269|PubMed:9558343}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 3'-end 2'-deoxyribonucleotidyl-deoxyribonucleotide-DNA + H2O CC = a 3'-end 2'-deoxyribonucleotide-DNA + a 2'-deoxyribonucleoside 5'- CC phosphate + H(+); Xref=Rhea:RHEA:77911, Rhea:RHEA-COMP:13863, CC Rhea:RHEA-COMP:19009, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:65317, ChEBI:CHEBI:138148, ChEBI:CHEBI:228185; CC Evidence={ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477094, CC ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:26095671, CC ECO:0000269|PubMed:9558343}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:77912; CC Evidence={ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477094, CC ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:26095671, CC ECO:0000269|PubMed:9558343}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 5'-end 2'-deoxyribose-2'-deoxyribonucleotide-DNA = (2E,4S)- CC 4-hydroxypenten-2-al-5-phosphate + a 5'-end 5'-phospho-2'- CC deoxyribonucleoside-DNA + H(+); Xref=Rhea:RHEA:76255, Rhea:RHEA- CC COMP:13180, Rhea:RHEA-COMP:18657, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:136412, ChEBI:CHEBI:195194, ChEBI:CHEBI:195195; CC Evidence={ECO:0000269|PubMed:9770471}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76256; CC Evidence={ECO:0000269|PubMed:9770471}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:26056153}; CC -!- ACTIVITY REGULATION: Inhibited by dideoxynucleotides such as antiviral CC agent zalcitabine. {ECO:0000269|PubMed:26056153}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.011 uM for dTTP (POLG polymerase activity at matched G:C primer- CC template) {ECO:0000269|PubMed:11504725}; CC KM=0.015 uM for dTTP (POLG:POLG2 polymerase activity at matched G:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=5.5 uM for dTTP (POLG polymerase activity at mismatched A:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=7.6 uM for dTTP (POLG:POLG2 polymerase activity at mismatched A:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=10 uM for dTTP (POLG polymerase activity at mismatched T:C primer- CC template) {ECO:0000269|PubMed:11504725}; CC KM=5.5 uM for dTTP (POLG:POLG2 polymerase activity at mismatched T:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=13 uM for dTTP (POLG polymerase activity at mismatched G:G primer- CC template) {ECO:0000269|PubMed:11504725}; CC KM=11 uM for dTTP (POLG:POLG2 polymerase activity at mismatched G:G CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=55 uM for dTTP (POLG polymerase activity at mismatched C:C primer- CC template) {ECO:0000269|PubMed:11504725}; CC KM=11 uM for dTTP (POLG:POLG2 polymerase activity at mismatched C:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC -!- SUBUNIT: Heterotrimer composed of a catalytic subunit and a homodimer CC of accessory subunits (POLG:POLG2) (PubMed:11477093, PubMed:11477094, CC PubMed:15167897, PubMed:19837034, PubMed:26056153, PubMed:37202477). CC Interacts with TTC3 (PubMed:29290964). Interacts with LIG3 CC (PubMed:33855352). {ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:15167897, CC ECO:0000269|PubMed:19837034, ECO:0000269|PubMed:26056153, CC ECO:0000269|PubMed:37202477}. CC -!- INTERACTION: CC P54098; Q9UHN1: POLG2; NbExp=15; IntAct=EBI-852624, EBI-852642; CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:10827171, CC ECO:0000269|PubMed:18063578}. Mitochondrion matrix, mitochondrion CC nucleoid {ECO:0000269|PubMed:18063578}. CC -!- DOMAIN: The polymerase domain encompasses three conserved active site CC motifs: Pol A (residues 887-896), Pol B (residues 943-958) and Pol C CC (residues 1134-1141). Binds the incoming dNTPs and undergoes an open to CC close coformation change to catalyze the formation of phosphodiester CC bond. {ECO:0000269|PubMed:26056153, ECO:0000303|PubMed:15189144, CC ECO:0000303|PubMed:8884268}. CC -!- DOMAIN: The 3' -> 5' exonuclease domain comprises three conserved CC active site motifs: Exo I (residues 196-200), Exo II (residues 267-275) CC and Exo III (residues 395-403). Proofreads the newly synthesized DNA CC strand. {ECO:0000269|PubMed:37202477, ECO:0000303|PubMed:15189144, CC ECO:0000303|PubMed:8884268}. CC -!- DOMAIN: The trigger loop contracts to enable correctly matched primer- CC template pair entry into the polymerase domain and extends to preclude CC the mismatched one. {ECO:0000269|PubMed:37202477}. CC -!- DOMAIN: The accessory determinant domain (AID) interacts with POLG2 CC proximal monomer. {ECO:0000269|PubMed:26056153}. CC -!- POLYMORPHISM: The poly-Gln region seems to be polymorphic. CC {ECO:0000269|Ref.3, ECO:0000269|Ref.4}. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 1 (PEOA1) [MIM:157640]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:11897778, CC ECO:0000269|PubMed:12210792, ECO:0000269|PubMed:15351195, CC ECO:0000269|PubMed:15534189, ECO:0000269|PubMed:17420318, CC ECO:0000269|PubMed:17846414, ECO:0000269|PubMed:18575922}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal recessive, 1 (PEOB1) [MIM:258450]: A severe form CC of progressive external ophthalmoplegia, a disorder characterized by CC progressive weakness of ocular muscles and levator muscle of the upper CC eyelid. It is clinically more heterogeneous than the autosomal dominant CC forms. {ECO:0000269|PubMed:11431686, ECO:0000269|PubMed:12210792, CC ECO:0000269|PubMed:12707443, ECO:0000269|PubMed:12872260, CC ECO:0000269|PubMed:12975295, ECO:0000269|PubMed:14635118, CC ECO:0000269|PubMed:15349879, ECO:0000269|PubMed:15351195, CC ECO:0000269|PubMed:15477547, ECO:0000269|PubMed:15917273, CC ECO:0000269|PubMed:16401742, ECO:0000269|PubMed:16621917, CC ECO:0000269|PubMed:16634032, ECO:0000269|PubMed:16639411, CC ECO:0000269|PubMed:21301859, ECO:0000269|PubMed:26095671}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Sensory ataxic neuropathy dysarthria and ophthalmoparesis CC (SANDO) [MIM:607459]: A systemic disorder resulting from mitochondrial CC dysfunction associated with mitochondrial depletion in skeletal muscle CC and peripheral nerve tissue. The clinical triad of symptoms consists of CC sensory ataxic neuropathy, dysarthria, and ophthalmoparesis. However, CC the phenotype varies widely, even within the same family, and can also CC include myopathy, seizures, and hearing loss. CC {ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:14745080, CC ECO:0000269|PubMed:15477547, ECO:0000269|PubMed:15824347, CC ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:16080118, CC ECO:0000269|PubMed:16621917, ECO:0000269|PubMed:16639411, CC ECO:0000269|PubMed:16919951}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 4A (MTDPS4A) CC [MIM:203700]: An autosomal recessive hepatocerebral syndrome due to CC mitochondrial dysfunction. The typical course of the disease includes CC severe developmental delay, intractable seizures, liver failure, and CC death in childhood. Refractory seizures, cortical blindness, CC progressive liver dysfunction, and acute liver failure after exposure CC to valproic acid are considered diagnostic features. The CC neuropathological hallmarks are neuronal loss, spongiform degeneration, CC and astrocytosis of the visual cortex. Liver biopsy results show CC steatosis, often progressing to cirrhosis. CC {ECO:0000269|PubMed:15122711, ECO:0000269|PubMed:15689359, CC ECO:0000269|PubMed:15929042, ECO:0000269|PubMed:16621917, CC ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18828154, CC ECO:0000269|PubMed:20400524, ECO:0000269|PubMed:22000311, CC ECO:0000269|PubMed:25129007}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 4B (MTDPS4B) CC [MIM:613662]: An autosomal recessive progressive multisystem disorder CC due to mitochondrial dysfunction. It is clinically characterized by CC chronic gastrointestinal dysmotility and pseudo-obstruction, cachexia, CC progressive external ophthalmoplegia, axonal sensory ataxic neuropathy, CC and muscle weakness. {ECO:0000269|PubMed:12825077, CC ECO:0000269|PubMed:19307547}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive CC neurodegenerative disorder characterized by the presence of focal, CC bilateral lesions in one or more areas of the central nervous system CC including the brainstem, thalamus, basal ganglia, cerebellum and spinal CC cord. Clinical features depend on which areas of the central nervous CC system are involved and include subacute onset of psychomotor CC retardation, hypotonia, ataxia, weakness, vision loss, eye movement CC abnormalities, seizures, and dysphagia. {ECO:0000269|PubMed:18828154, CC ECO:0000269|PubMed:26095671}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Spinocerebellar ataxia with epilepsy (SCAE) [MIM:607459]: An CC autosomal recessive syndrome characterized by headaches and/or seizures CC manifesting in childhood or adolescence, cerebellar and sensory ataxia, CC dysarthria, and myoclonus manifesting in early adulthood. CC Neuropathological findings include spinocerebellar degeneration CC associated with cortical neuronal degeneration in advanced cases. CC {ECO:0000269|PubMed:14694057, ECO:0000269|PubMed:20400524, CC ECO:0000269|PubMed:26942291}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the DNA polymerase type-A family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U60325; AAC50712.1; -; mRNA. DR EMBL; X98093; CAA66719.1; -; mRNA. DR EMBL; D84103; BAA12223.1; -; mRNA. DR EMBL; AF497906; AAM77583.1; -; Genomic_DNA. DR EMBL; BC042571; AAH42571.1; -; mRNA. DR EMBL; BC050559; AAH50559.1; -; mRNA. DR CCDS; CCDS10350.1; -. DR PIR; G02750; G02750. DR RefSeq; NP_001119603.1; NM_001126131.2. DR RefSeq; NP_002684.1; NM_002693.3. DR PDB; 3IKM; X-ray; 3.24 A; A/D=70-1239. DR PDB; 4ZTU; X-ray; 3.30 A; A=30-1239. DR PDB; 4ZTZ; X-ray; 3.44 A; A=30-1239. DR PDB; 5C51; X-ray; 3.43 A; A=25-1239. DR PDB; 5C52; X-ray; 3.64 A; A=25-1239. DR PDB; 5C53; X-ray; 3.57 A; A=25-1239. DR PDB; 8D33; EM; 2.46 A; A=1-1239. DR PDB; 8D37; EM; 2.65 A; A=1-1239. DR PDB; 8D3R; EM; 3.04 A; A=1-1239. DR PDB; 8D42; EM; 2.91 A; A=1-1239. DR PDB; 8G5I; EM; 2.75 A; A=1-1239. DR PDB; 8G5J; EM; 2.63 A; A=1-1239. DR PDB; 8G5K; EM; 2.90 A; A=1-1239. DR PDB; 8G5L; EM; 3.00 A; A=1-1239. DR PDB; 8G5M; EM; 2.58 A; A=1-1239. DR PDB; 8G5N; EM; 2.73 A; A=1-1239. DR PDB; 8G5O; EM; 2.61 A; A=1-1239. DR PDB; 8G5P; EM; 2.78 A; A=1-1239. DR PDB; 8T7E; EM; 3.08 A; A=1-1239. DR PDB; 8UDK; X-ray; 3.43 A; A=1-1239. DR PDB; 8UDL; EM; 2.37 A; A=1-1239. DR PDB; 8V54; EM; 4.10 A; A=26-1239. DR PDB; 8V55; EM; 4.20 A; A=26-1239. DR PDB; 8V5D; EM; 3.00 A; A=26-1239. DR PDB; 8V5R; EM; 3.00 A; A=26-1239. DR PDB; 9GGB; EM; 2.63 A; A=26-1239. DR PDB; 9GGC; EM; 2.39 A; A=26-1239. DR PDB; 9GGD; EM; 2.67 A; A=26-1239. DR PDB; 9GGE; EM; 2.69 A; A=26-1239. DR PDB; 9GGF; EM; 2.65 A; A=26-1239. DR PDB; 9IC1; EM; 2.73 A; A=26-1239. DR PDB; 9IC3; EM; 2.96 A; A=26-1239. DR PDBsum; 3IKM; -. DR PDBsum; 4ZTU; -. DR PDBsum; 4ZTZ; -. DR PDBsum; 5C51; -. DR PDBsum; 5C52; -. DR PDBsum; 5C53; -. DR PDBsum; 8D33; -. DR PDBsum; 8D37; -. DR PDBsum; 8D3R; -. DR PDBsum; 8D42; -. DR PDBsum; 8G5I; -. DR PDBsum; 8G5J; -. DR PDBsum; 8G5K; -. DR PDBsum; 8G5L; -. DR PDBsum; 8G5M; -. DR PDBsum; 8G5N; -. DR PDBsum; 8G5O; -. DR PDBsum; 8G5P; -. DR PDBsum; 8T7E; -. DR PDBsum; 8UDK; -. DR PDBsum; 8UDL; -. DR PDBsum; 8V54; -. DR PDBsum; 8V55; -. DR PDBsum; 8V5D; -. DR PDBsum; 8V5R; -. DR PDBsum; 9GGB; -. DR PDBsum; 9GGC; -. DR PDBsum; 9GGD; -. DR PDBsum; 9GGE; -. DR PDBsum; 9GGF; -. DR PDBsum; 9IC1; -. DR PDBsum; 9IC3; -. DR AlphaFoldDB; P54098; -. DR EMDB; EMD-27154; -. DR EMDB; EMD-27155; -. DR EMDB; EMD-27163; -. DR EMDB; EMD-27172; -. DR EMDB; EMD-29745; -. DR EMDB; EMD-29746; -. DR EMDB; EMD-29747; -. DR EMDB; EMD-29748; -. DR EMDB; EMD-29749; -. DR EMDB; EMD-29750; -. DR EMDB; EMD-29751; -. DR EMDB; EMD-29752; -. DR EMDB; EMD-41091; -. DR EMDB; EMD-42150; -. DR EMDB; EMD-42842; -. DR EMDB; EMD-42979; -. DR EMDB; EMD-42980; -. DR EMDB; EMD-42982; -. DR EMDB; EMD-42984; -. DR EMDB; EMD-51326; -. DR EMDB; EMD-51327; -. DR EMDB; EMD-51328; -. DR EMDB; EMD-51329; -. DR EMDB; EMD-51330; -. DR EMDB; EMD-52824; -. DR EMDB; EMD-52828; -. DR SMR; P54098; -. DR BioGRID; 111424; 116. DR ComplexPortal; CPX-2093; Mitochondrial DNA polymerase gamma complex. DR FunCoup; P54098; 1006. DR IntAct; P54098; 64. DR MINT; P54098; -. DR STRING; 9606.ENSP00000399851; -. DR BindingDB; P54098; -. DR ChEMBL; CHEMBL2732; -. DR DrugBank; DB12151; Brincidofovir. DR DrugCentral; P54098; -. DR GlyGen; P54098; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P54098; -. DR PhosphoSitePlus; P54098; -. DR SwissPalm; P54098; -. DR BioMuta; POLG; -. DR DMDM; 1706507; -. DR jPOST; P54098; -. DR MassIVE; P54098; -. DR PaxDb; 9606-ENSP00000268124; -. DR PeptideAtlas; P54098; -. DR ProteomicsDB; 56642; -. DR Pumba; P54098; -. DR Antibodypedia; 28558; 222 antibodies from 35 providers. DR DNASU; 5428; -. DR Ensembl; ENST00000268124.11; ENSP00000268124.5; ENSG00000140521.18. DR Ensembl; ENST00000442287.6; ENSP00000399851.2; ENSG00000140521.18. DR Ensembl; ENST00000636937.2; ENSP00000516154.1; ENSG00000140521.18. DR GeneID; 5428; -. DR KEGG; hsa:5428; -. DR MANE-Select; ENST00000268124.11; ENSP00000268124.5; NM_002693.3; NP_002684.1. DR UCSC; uc002bnr.5; human. DR AGR; HGNC:9179; -. DR ClinPGx; PA33500; -. DR CTD; 5428; -. DR DisGeNET; 5428; -. DR GeneCards; POLG; -. DR GeneReviews; POLG; -. DR HGNC; HGNC:9179; POLG. DR HPA; ENSG00000140521; Low tissue specificity. DR MalaCards; POLG; -. DR MIM; 157640; phenotype. DR MIM; 174763; gene. DR MIM; 203700; phenotype. DR MIM; 256000; phenotype. DR MIM; 258450; phenotype. DR MIM; 607459; phenotype. DR MIM; 613662; phenotype. DR OpenTargets; ENSG00000140521; -. DR Orphanet; 726; Alpers-Huttenlocher syndrome. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR Orphanet; 254886; Autosomal recessive progressive external ophthalmoplegia. DR Orphanet; 298; Mitochondrial neurogastrointestinal encephalomyopathy. DR Orphanet; 402082; Progressive myoclonic epilepsy type 5. DR Orphanet; 94125; Recessive mitochondrial ataxia syndrome. DR Orphanet; 70595; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome. DR Orphanet; 254881; Spinocerebellar ataxia with epilepsy. DR VEuPathDB; HostDB:ENSG00000140521; -. DR eggNOG; KOG3657; Eukaryota. DR GeneTree; ENSGT00390000000453; -. DR HOGENOM; CLU_001524_2_2_1; -. DR InParanoid; P54098; -. DR OMA; AMHITNL; -. DR OrthoDB; 5588663at2759; -. DR PAN-GO; P54098; 4 GO annotations based on evolutionary models. DR PhylomeDB; P54098; -. DR PathwayCommons; P54098; -. DR Reactome; R-HSA-9913635; Strand-asynchronous mitochondrial DNA replication. DR SignaLink; P54098; -. DR SIGNOR; P54098; -. DR Agora; ENSG00000140521; -. DR BioGRID-ORCS; 5428; 224 hits in 1160 CRISPR screens. DR ChiTaRS; POLG; human. DR GeneWiki; POLG; -. DR GenomeRNAi; 5428; -. DR Pharos; P54098; Tchem. DR PRO; PR:P54098; -. DR Proteomes; UP000005640; Chromosome 15. DR RNAct; P54098; protein. DR Bgee; ENSG00000140521; Expressed in granulocyte and 212 other cell types or tissues. DR ExpressionAtlas; P54098; baseline and differential. DR GO; GO:0005760; C:gamma DNA polymerase complex; IDA:UniProtKB. DR GO; GO:0000262; C:mitochondrial chromosome; IDA:FlyBase. DR GO; GO:0005759; C:mitochondrial matrix; IDA:ComplexPortal. DR GO; GO:0042645; C:mitochondrial nucleoid; IDA:BHF-UCL. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0032991; C:protein-containing complex; IDA:MGI. DR GO; GO:0008408; F:3'-5' exonuclease activity; IDA:FlyBase. DR GO; GO:0051575; F:5'-deoxyribose-5-phosphate lyase activity; IDA:UniProtKB. DR GO; GO:0003682; F:chromatin binding; IDA:UniProtKB. DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB. DR GO; GO:0003887; F:DNA-directed DNA polymerase activity; IDA:UniProtKB. DR GO; GO:0002020; F:protease binding; IPI:UniProtKB. DR GO; GO:0008310; F:single-stranded DNA 3'-5' DNA exonuclease activity; IDA:UniProtKB. DR GO; GO:0006284; P:base-excision repair; IDA:UniProtKB. DR GO; GO:0006287; P:base-excision repair, gap-filling; IDA:MGI. DR GO; GO:0006259; P:DNA metabolic process; TAS:ProtInc. DR GO; GO:0045004; P:DNA replication proofreading; IDA:UniProtKB. DR GO; GO:0006261; P:DNA-templated DNA replication; IDA:UniProtKB. DR GO; GO:0006264; P:mitochondrial DNA replication; IDA:FlyBase. DR CDD; cd08641; DNA_pol_gammaA; 1. DR FunFam; 1.10.150.20:FF:000024; DNA polymerase gamma, catalytic subunit; 1. DR FunFam; 1.20.5.3960:FF:000002; DNA polymerase gamma, catalytic subunit; 1. DR FunFam; 3.30.420.390:FF:000001; DNA polymerase gamma, catalytic subunit; 1. DR FunFam; 3.30.420.390:FF:000002; DNA polymerase gamma, catalytic subunit; 1. DR Gene3D; 1.20.5.3960; -; 1. DR Gene3D; 3.30.420.390; -; 2. DR Gene3D; 3.30.70.370; -; 1. DR Gene3D; 1.10.150.20; 5' to 3' exonuclease, C-terminal subdomain; 1. DR InterPro; IPR019760; DNA-dir_DNA_pol_A_CS. DR InterPro; IPR002297; DNA-dir_DNA_pol_A_mt. DR InterPro; IPR001098; DNA-dir_DNA_pol_A_palm_dom. DR InterPro; IPR043502; DNA/RNA_pol_sf. DR InterPro; IPR041336; DNApol_Exo. DR InterPro; IPR047580; POLG_palm_dom. DR InterPro; IPR012337; RNaseH-like_sf. DR PANTHER; PTHR10267; DNA POLYMERASE SUBUNIT GAMMA-1; 1. DR PANTHER; PTHR10267:SF0; DNA POLYMERASE SUBUNIT GAMMA-1; 1. DR Pfam; PF18136; DNApol_Exo; 1. DR PIRSF; PIRSF000797; DNA_pol_mt; 1. DR PRINTS; PR00867; DNAPOLG. DR SMART; SM00482; POLAc; 1. DR SUPFAM; SSF56672; DNA/RNA polymerases; 1. DR SUPFAM; SSF53098; Ribonuclease H-like; 1. DR PROSITE; PS00447; DNA_POLYMERASE_A; 1. PE 1: Evidence at protein level; KW 3D-structure; Disease variant; DNA replication; DNA-binding; KW DNA-directed DNA polymerase; Epilepsy; Hydrolase; Leigh syndrome; Lyase; KW Magnesium; Mitochondrion; Mitochondrion nucleoid; Neurodegeneration; KW Neuropathy; Nucleotidyltransferase; Primary mitochondrial disease; KW Progressive external ophthalmoplegia; Proteomics identification; KW Reference proteome; Transferase. FT CHAIN 1..1239 FT /note="DNA polymerase subunit gamma-1" FT /id="PRO_0000101270" FT REGION 1..68 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 43..55 FT /note="Does not contribute to polymerase and exonuclease FT enzymatic activities" FT /evidence="ECO:0000269|PubMed:10827171" FT REGION 318..340 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 506..531 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 510..571 FT /note="Accessory-interacting determinant" FT /evidence="ECO:0000269|PubMed:26056153" FT REGION 858..864 FT /note="Trigger loop" FT /evidence="ECO:0000269|PubMed:37202477" FT MOTIF 196..200 FT /note="Exo I" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 267..275 FT /note="Exo II" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 395..403 FT /note="Exo III" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 887..896 FT /note="Pol A" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 943..958 FT /note="Pol B" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 1134..1141 FT /note="Pol C" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT COMPBIAS 9..36 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 44..60 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 198 FT /note="Exonuclease activity" FT /evidence="ECO:0000269|PubMed:37202477" FT BINDING 306 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 579 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 593 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 754 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 763 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 768 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 806 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 849 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 863 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 869 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 890 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 890 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 890 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 891 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 891 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 893 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 895 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 943 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 947 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 951 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 1094 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 1095 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 1135 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 1135 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 1135 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT SITE 853 FT /note="Critical for replication fidelity and mismatch FT recognition" FT /evidence="ECO:0000269|PubMed:37202477" FT SITE 1102 FT /note="Critical for replication fidelity and mismatch FT recognition" FT /evidence="ECO:0000269|PubMed:37202477" FT VARIANT 3 FT /note="R -> P (in PEOB1 and SANDO; dbSNP:rs121918045)" FT /evidence="ECO:0000269|PubMed:11431686, FT ECO:0000269|PubMed:12565911" FT /id="VAR_012153" FT VARIANT 18 FT /note="P -> S (in dbSNP:rs3087373)" FT /id="VAR_014904" FT VARIANT 55 FT /note="Q -> QQ" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_019265" FT VARIANT 55 FT /note="Q -> QQQ" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_019266" FT VARIANT 193 FT /note="R -> Q (in dbSNP:rs3176162)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_019267" FT VARIANT 227 FT /note="R -> W (in PEOB1 and MTDPS4B; dbSNP:rs121918056)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:15349879, ECO:0000269|PubMed:19307547" FT /id="VAR_023663" FT VARIANT 232 FT /note="R -> G (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:15689359" FT /id="VAR_058870" FT VARIANT 232 FT /note="R -> H (in LS; displays markedly increased FT exonuclease activity and reduced polymerization activity; FT produces ligatable 5'-ends; dbSNP:rs113994093)" FT /evidence="ECO:0000269|PubMed:18828154, FT ECO:0000269|PubMed:26095671" FT /id="VAR_058871" FT VARIANT 244 FT /note="L -> P (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:15689359" FT /id="VAR_058872" FT VARIANT 251 FT /note="T -> I (in PEOB1, MTDPS4A and MTDPS4B; FT dbSNP:rs113994094)" FT /evidence="ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:12707443, ECO:0000269|PubMed:12825077, FT ECO:0000269|PubMed:14635118, ECO:0000269|PubMed:18828154" FT /id="VAR_023664" FT VARIANT 268 FT /note="G -> A (in PEOB1; sporadic case; displays mildly FT reduced exonuclease activity; does not affect the FT polymerization activity or 5'-end ligation; FT dbSNP:rs61752784)" FT /evidence="ECO:0000269|PubMed:14635118, FT ECO:0000269|PubMed:26095671" FT /id="VAR_058873" FT VARIANT 275 FT /note="R -> Q (found in a patient with epileptic FT encephalopathy, developmental delay and moderate FT intellectual disability; uncertain significance; displays FT mildly reduced exonuclease activity; reduced polymerization FT activity; reduced DNA-binding affinity; does not affect 5'- FT end ligation; dbSNP:rs1555453950)" FT /evidence="ECO:0000269|PubMed:26095671, FT ECO:0000269|PubMed:30552426" FT /id="VAR_088657" FT VARIANT 277 FT /note="H -> L (in PEOB1; uncertain significance; does not FT affect exonuclease activity; does not affect polymerization FT activity; does not affect 5'-end ligation; FT dbSNP:rs138929605)" FT /evidence="ECO:0000269|PubMed:21301859, FT ECO:0000269|PubMed:26095671" FT /id="VAR_088658" FT VARIANT 303 FT /note="G -> R (in MTDPS4A; likely pathogenic; results in FT loss of exonuclease activity and formation of an FT unligatable 5'-flap; displays low polymerization activity FT and reduced DNA-binding affinity; dbSNP:rs749799663)" FT /evidence="ECO:0000269|PubMed:20400524, FT ECO:0000269|PubMed:26095671" FT /id="VAR_088659" FT VARIANT 304 FT /note="L -> R (in PEOB1 and SANDO; results in loss of FT exonuclease activity and formation of an unligatable 5'- FT flap; displays low polymerization activity and reduced DNA- FT binding affinity; dbSNP:rs121918044)" FT /evidence="ECO:0000269|PubMed:11431686, FT ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:16639411, FT ECO:0000269|PubMed:26095671" FT /id="VAR_012154" FT VARIANT 304 FT /note="L -> SANDO (in PEOB1)" FT /id="VAR_058874" FT VARIANT 305 FT /note="S -> R (in MTDPS4A; likely pathogenic; results in FT loss of exonuclease activity and formation of an FT unligatable 5'-flap; displays low polymerization activity FT and reduced DNA-binding affinity; dbSNP:rs769410130)" FT /evidence="ECO:0000269|PubMed:22000311, FT ECO:0000269|PubMed:26095671" FT /id="VAR_088660" FT VARIANT 308 FT /note="Q -> H (in PEOB1; sporadic case; dbSNP:rs745539599)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058875" FT VARIANT 309 FT /note="R -> L (in PEOB1)" FT /evidence="ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:15349879" FT /id="VAR_023665" FT VARIANT 312 FT /note="W -> R (in PEOB1; sporadic case)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:14635118" FT /id="VAR_023666" FT VARIANT 324 FT /note="P -> S (in dbSNP:rs2307437)" FT /id="VAR_014905" FT VARIANT 380 FT /note="G -> D (in PEOB1)" FT /evidence="ECO:0000269|PubMed:16639411" FT /id="VAR_058876" FT VARIANT 431 FT /note="G -> V (in PEOB1; sporadic case)" FT /evidence="ECO:0000269|PubMed:12707443" FT /id="VAR_023667" FT VARIANT 463 FT /note="L -> F (in dbSNP:rs150828914)" FT /evidence="ECO:0000269|PubMed:17420318" FT /id="VAR_058877" FT VARIANT 467 FT /note="A -> T (in PEOB1, SANDO, SCAE and MTDPS4A; FT pathogenic; results in clearly decreased activity, DNA FT binding and processivity of the polymerase; FT dbSNP:rs113994095)" FT /evidence="ECO:0000269|PubMed:11431686, FT ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:14635118, ECO:0000269|PubMed:14694057, FT ECO:0000269|PubMed:15122711, ECO:0000269|PubMed:15477547, FT ECO:0000269|PubMed:15689359, ECO:0000269|PubMed:15824347, FT ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:16639411, FT ECO:0000269|PubMed:18828154, ECO:0000269|PubMed:20400524, FT ECO:0000269|PubMed:22000311, ECO:0000269|PubMed:26942291" FT /id="VAR_012155" FT VARIANT 468 FT /note="N -> D (in PEOB1; dbSNP:rs145843073)" FT /evidence="ECO:0000269|PubMed:15351195" FT /id="VAR_023668" FT VARIANT 497 FT /note="Q -> H (in SANDO and SCAE; dbSNP:rs121918052)" FT /evidence="ECO:0000269|PubMed:15824347, FT ECO:0000269|PubMed:26942291" FT /id="VAR_023669" FT VARIANT 511 FT /note="S -> N (in PEOA1; dbSNP:rs121918055)" FT /evidence="ECO:0000269|PubMed:17420318" FT /id="VAR_058878" FT VARIANT 517 FT /note="G -> V (in SANDO; dbSNP:rs61752783)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058879" FT VARIANT 546 FT /note="R -> C (in dbSNP:rs2307447)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_014906" FT VARIANT 562 FT /note="R -> Q (in PEOB1; sporadic case; dbSNP:rs781168350)" FT /evidence="ECO:0000269|PubMed:14635118" FT /id="VAR_058880" FT VARIANT 574 FT /note="R -> W (in PEOB1; sporadic case; dbSNP:rs774474723)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058881" FT VARIANT 579 FT /note="R -> W (in PEOB1; dbSNP:rs556925652)" FT /evidence="ECO:0000269|PubMed:12975295" FT /id="VAR_023670" FT VARIANT 587 FT /note="P -> L (in PEOB1, MTDPS4A and MTDPS4B; FT dbSNP:rs113994096)" FT /evidence="ECO:0000269|PubMed:12825077, FT ECO:0000269|PubMed:12975295, ECO:0000269|PubMed:14635118, FT ECO:0000269|PubMed:15349879, ECO:0000269|PubMed:15689359, FT ECO:0000269|PubMed:18828154" FT /id="VAR_023671" FT VARIANT 603 FT /note="M -> L (in PEOB1)" FT /evidence="ECO:0000269|PubMed:16401742" FT /id="VAR_058882" FT VARIANT 627 FT /note="R -> Q (in SANDO; shows DNA binding affinity and FT processivities similar to the controls; dbSNP:rs375305567)" FT /evidence="ECO:0000269|PubMed:15917273" FT /id="VAR_058883" FT VARIANT 627 FT /note="R -> W (in SANDO; sporadic case; dbSNP:rs121918046)" FT /evidence="ECO:0000269|PubMed:12565911" FT /id="VAR_023672" FT VARIANT 648 FT /note="P -> R (in PEOB1; sporadic case; also in SANDO; FT dbSNP:rs796052906)" FT /evidence="ECO:0000269|PubMed:16621917, FT ECO:0000269|PubMed:16919951" FT /id="VAR_058884" FT VARIANT 662 FT /note="E -> K (in dbSNP:rs2307450)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_014907" FT VARIANT 737 FT /note="G -> R (in PEOB1; with absence of progressive FT external ophthalmoplegia; dbSNP:rs121918054)" FT /evidence="ECO:0000269|PubMed:16634032" FT /id="VAR_058885" FT VARIANT 748 FT /note="W -> S (in SANDO, SCAE and MTDPS4A; pathogenic; FT dbSNP:rs113994097)" FT /evidence="ECO:0000269|PubMed:15477547, FT ECO:0000269|PubMed:15824347, ECO:0000269|PubMed:15929042, FT ECO:0000269|PubMed:16080118, ECO:0000269|PubMed:16639411, FT ECO:0000269|PubMed:18828154, ECO:0000269|PubMed:20400524, FT ECO:0000269|PubMed:22000311, ECO:0000269|PubMed:26942291" FT /id="VAR_023673" FT VARIANT 767 FT /note="A -> D (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058886" FT VARIANT 807 FT /note="R -> C (in SANDO; dbSNP:rs769827124)" FT /evidence="ECO:0000269|PubMed:16919951" FT /id="VAR_058887" FT VARIANT 807 FT /note="R -> P (in PEOB1; sporadic case)" FT /evidence="ECO:0000269|PubMed:14635118" FT /id="VAR_058888" FT VARIANT 831 FT /note="Y -> C (in PEOA1 and MTDPS4A; uncertain FT significance; dbSNP:rs41549716)" FT /evidence="ECO:0000269|PubMed:15534189, FT ECO:0000269|PubMed:17846414, ECO:0000269|PubMed:18828154" FT /id="VAR_023674" FT VARIANT 848 FT /note="G -> S (in PEOB1, MTDPS4A, MTDPS4B and LS; also FT found in a patient with epileptic encephalopathy, FT developmental delay and moderate intellectual disability; FT dbSNP:rs113994098)" FT /evidence="ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:12872260, ECO:0000269|PubMed:15689359, FT ECO:0000269|PubMed:15929042, ECO:0000269|PubMed:18828154, FT ECO:0000269|PubMed:19307547, ECO:0000269|PubMed:20400524, FT ECO:0000269|PubMed:22000311, ECO:0000269|PubMed:30552426" FT /id="VAR_023675" FT VARIANT 852 FT /note="R -> C (in MTDPS4A; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:22000311" FT /id="VAR_088688" FT VARIANT 853 FT /note="R -> W (in PEOB1; with absence of progressive FT external ophthalmoplegia; dbSNP:rs121918053)" FT /evidence="ECO:0000269|PubMed:16401742, FT ECO:0000269|PubMed:16634032" FT /id="VAR_058889" FT VARIANT 864 FT /note="N -> S (in MTDPS4B; dbSNP:rs121918050)" FT /evidence="ECO:0000269|PubMed:12825077" FT /id="VAR_023676" FT VARIANT 879 FT /note="Q -> H (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058890" FT VARIANT 885 FT /note="T -> S (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058891" FT VARIANT 889 FT /note="A -> T (in PEOB1; dbSNP:rs763393580)" FT /evidence="ECO:0000269|PubMed:12975295" FT /id="VAR_023677" FT VARIANT 914 FT /note="T -> P (in MTDPS4A; dbSNP:rs139590686)" FT /evidence="ECO:0000269|PubMed:16621917, FT ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18828154" FT /id="VAR_058892" FT VARIANT 923 FT /note="G -> D (in PEOA1)" FT /evidence="ECO:0000269|PubMed:12210792" FT /id="VAR_023678" FT VARIANT 932 FT /note="H -> Y (in SANDO and PEOB1; sporadic case; FT dbSNP:rs121918048)" FT /evidence="ECO:0000269|PubMed:14635118, FT ECO:0000269|PubMed:14745080" FT /id="VAR_023679" FT VARIANT 943 FT /note="R -> C (in PEOB1; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:21301859" FT /id="VAR_088689" FT VARIANT 943 FT /note="R -> H (in PEOA1)" FT /evidence="ECO:0000269|PubMed:12210792" FT /id="VAR_023680" FT VARIANT 953 FT /note="R -> C (in PEOA1; dbSNP:rs11546842)" FT /evidence="ECO:0000269|PubMed:15351195" FT /id="VAR_023681" FT VARIANT 955 FT /note="Y -> C (in PEOA1, PEOB1 and SANDO; 45-fold decrease FT in apparent binding affinity for the incoming nucleoside FT triphosphate; 2-fold less accurate for basepair FT substitutions than wild-type; dbSNP:rs113994099)" FT /evidence="ECO:0000269|PubMed:11431686, FT ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:15351195" FT /id="VAR_012156" FT VARIANT 957 FT /note="A -> P (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:15689359" FT /id="VAR_058893" FT VARIANT 957 FT /note="A -> S (in PEOA1; dbSNP:rs121918051)" FT /evidence="ECO:0000269|PubMed:12210792" FT /id="VAR_023682" FT VARIANT 966 FT /note="L -> R (in MTDPS4A; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:22000311" FT /id="VAR_088690" FT VARIANT 1047 FT /note="R -> Q (in PEOB1; sporadic case; dbSNP:rs768028281)" FT /evidence="ECO:0000269|PubMed:12707443" FT /id="VAR_023683" FT VARIANT 1051 FT /note="G -> R (in SANDO; dbSNP:rs121918049)" FT /evidence="ECO:0000269|PubMed:14745080" FT /id="VAR_023684" FT VARIANT 1076 FT /note="G -> V (in PEOB1)" FT /evidence="ECO:0000269|PubMed:12975295" FT /id="VAR_023685" FT VARIANT 1096 FT /note="R -> C (in PEOB1 and MTDPS4A; dbSNP:rs201732356)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:25129007" FT /id="VAR_023686" FT VARIANT 1096 FT /note="R -> H (in MTDPS4A; dbSNP:rs368435864)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058894" FT VARIANT 1104 FT /note="S -> C (in PEOB1; sporadic case; FT dbSNP:rs1010372555)" FT /evidence="ECO:0000269|PubMed:12707443" FT /id="VAR_023687" FT VARIANT 1105 FT /note="A -> T (in PEOB1; dbSNP:rs753410045)" FT /evidence="ECO:0000269|PubMed:15351195" FT /id="VAR_023688" FT VARIANT 1106 FT /note="V -> I (in PEOB1)" FT /evidence="ECO:0000269|PubMed:15349879" FT /id="VAR_023689" FT VARIANT 1110 FT /note="H -> Y (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:18828154" FT /id="VAR_058895" FT VARIANT 1134 FT /note="H -> R (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:18828154" FT /id="VAR_058896" FT VARIANT 1136 FT /note="E -> K (in MTDPS4A; dbSNP:rs56047213)" FT /evidence="ECO:0000269|PubMed:18828154" FT /id="VAR_065092" FT VARIANT 1142 FT /note="R -> W (in dbSNP:rs2307442)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_014908" FT VARIANT 1143 FT /note="E -> G (in dbSNP:rs2307441)" FT /evidence="ECO:0000269|PubMed:14635118, FT ECO:0000269|PubMed:15477547, ECO:0000269|PubMed:15689359, FT ECO:0000269|PubMed:16080118, ECO:0000269|PubMed:16639411, FT ECO:0000269|PubMed:18828154, ECO:0000269|Ref.4" FT /id="VAR_014909" FT VARIANT 1146 FT /note="R -> C (in PEOB1; uncertain significance; FT dbSNP:rs2307440)" FT /evidence="ECO:0000269|PubMed:16401742, ECO:0000269|Ref.4" FT /id="VAR_014910" FT VARIANT 1176 FT /note="S -> L (in PEOA1; dbSNP:rs776031396)" FT /evidence="ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:15349879" FT /id="VAR_023690" FT VARIANT 1184 FT /note="D -> N (in PEOB1; dbSNP:rs1131691575)" FT /evidence="ECO:0000269|PubMed:16401742" FT /id="VAR_058897" FT VARIANT 1186 FT /note="D -> H (in PEOA1)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065119" FT VARIANT 1191 FT /note="K -> N (in MTDPS4A; dbSNP:rs1085307741)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058898" FT VARIANT 1236 FT /note="Q -> H (in dbSNP:rs3087374)" FT /evidence="ECO:0000269|PubMed:12975295, FT ECO:0000269|PubMed:14635118, ECO:0000269|PubMed:15917273, FT ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18828154, FT ECO:0000269|Ref.4" FT /id="VAR_014911" FT MUTAGEN 198 FT /note="D->A: Abolishes exonuclease activity; when FT associated with A-200. Decreases polymerase exonucleolytic FT proofreading by 30-fold for the T:G mismatch and by 14-fold FT for the A:A mismatch; when associated with A-200. FT Significantly increases mitochondrial DNA mutation FT frequency. Does not affect DNA polymerase activity." FT /evidence="ECO:0000269|PubMed:10827171, FT ECO:0000269|PubMed:11504725, ECO:0000269|PubMed:37202477" FT MUTAGEN 200 FT /note="E->A: Abolishes exonuclease activity; when FT associated with A-198. Decreases polymerase exonucleolytic FT proofreading by 30-fold for the T:G mismatch and by 14-fold FT for the A:A mismatch; when associated with A-198." FT /evidence="ECO:0000269|PubMed:11477093, FT ECO:0000269|PubMed:11504725, ECO:0000269|PubMed:37202477" FT MUTAGEN 274 FT /note="D->A: Unable to idle at the 5'-end of the nascent FT DNA strand. Continues DNA synthesis into double-stranded FT DNA past the 5'-end creating a flap structure that cannot FT be ligated." FT /evidence="ECO:0000269|PubMed:26095671" FT MUTAGEN 498 FT /note="K->C: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:26056153" FT MUTAGEN 499 FT /note="K->C: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:26056153" FT MUTAGEN 501 FT /note="K->C: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:26056153" FT MUTAGEN 543..558 FT /note="Missing: Markedly decreases the stimulation by FT POLG2, resulting in impaired processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:19837034" FT MUTAGEN 549 FT /note="L->N: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:19837034" FT MUTAGEN 552 FT /note="L->N: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:19837034" FT MUTAGEN 553 FT /note="K->N: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:19837034" FT MUTAGEN 853 FT /note="R->A: Abolishes primer DNA extention in the presence FT of dNTPs. Impairs intrinsic polymerase processivity. FT Enhances exonuclease activity leading to primer DNA FT degradation." FT /evidence="ECO:0000269|PubMed:37202477" FT MUTAGEN 890 FT /note="D->N: Abolishes DNA polymerase activity." FT /evidence="ECO:0000269|PubMed:10827171" FT MUTAGEN 1135 FT /note="D->N: Abolishes DNA polymerase activity." FT /evidence="ECO:0000269|PubMed:10827171" FT HELIX 73..75 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 76..78 FT /evidence="ECO:0007829|PDB:8D42" FT HELIX 81..87 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 97..110 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 114..116 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 132..134 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 135..157 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 172..178 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 180..182 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 184..186 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 193..200 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 203..205 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 207..210 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 211..215 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 220..224 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 226..229 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 237..239 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 241..243 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 248..251 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 254..256 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 260..262 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 265..270 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 271..275 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 279..282 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 283..285 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 290..293 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 294..300 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 306..314 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 347..350 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 356..363 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 376..379 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 382..387 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 389..417 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 421..430 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 435..438 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 440..470 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 471..481 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 483..487 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 503..505 FT /evidence="ECO:0007829|PDB:5C51" FT STRAND 519..521 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 538..553 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 554..558 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 559..561 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 567..569 FT /evidence="ECO:0007829|PDB:8D37" FT HELIX 571..575 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 587..589 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 594..598 FT /evidence="ECO:0007829|PDB:8D3R" FT HELIX 599..602 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 606..609 FT /evidence="ECO:0007829|PDB:8V5R" FT STRAND 610..615 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 616..618 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 619..624 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 628..630 FT /evidence="ECO:0007829|PDB:8D37" FT HELIX 636..644 FT /evidence="ECO:0007829|PDB:3IKM" FT TURN 648..650 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 651..662 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 716..721 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 739..742 FT /evidence="ECO:0007829|PDB:8D3R" FT STRAND 743..745 FT /evidence="ECO:0007829|PDB:4ZTU" FT STRAND 748..751 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 755..757 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 765..767 FT /evidence="ECO:0007829|PDB:8V5R" FT HELIX 768..770 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 771..775 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 778..780 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 782..784 FT /evidence="ECO:0007829|PDB:8D3R" FT HELIX 787..809 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 814..816 FT /evidence="ECO:0007829|PDB:8D42" FT HELIX 818..820 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 823..826 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 833..835 FT /evidence="ECO:0007829|PDB:8V5R" FT STRAND 837..840 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 845..848 FT /evidence="ECO:0007829|PDB:4ZTU" FT TURN 849..851 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 853..855 FT /evidence="ECO:0007829|PDB:4ZTU" FT HELIX 859..861 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 867..869 FT /evidence="ECO:0007829|PDB:8D37" FT HELIX 872..877 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 884..890 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 894..907 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 909..911 FT /evidence="ECO:0007829|PDB:8D3R" FT HELIX 915..922 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 925..928 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 931..938 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 943..954 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 959..969 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 971..973 FT /evidence="ECO:0007829|PDB:8V5D" FT HELIX 975..989 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 991..993 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 997..999 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 1001..1009 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 1010..1013 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 1027..1030 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 1033..1035 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 1037..1040 FT /evidence="ECO:0007829|PDB:3IKM" FT TURN 1041..1046 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 1050..1052 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1055..1066 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1067..1069 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 1073..1075 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1081..1083 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 1085..1087 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1089..1092 FT /evidence="ECO:0007829|PDB:8D3R" FT HELIX 1093..1122 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1127..1132 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1134..1142 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1143..1145 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1146..1167 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1175..1177 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1183..1188 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1191..1194 FT /evidence="ECO:0007829|PDB:8D33" FT STRAND 1202..1204 FT /evidence="ECO:0007829|PDB:8D33" FT HELIX 1206..1209 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1216..1218 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1220..1227 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1232..1235 FT /evidence="ECO:0007829|PDB:3IKM" SQ SEQUENCE 1239 AA; 139562 MW; 2D9ECCD75AD6E01E CRC64; MSRLLWRKVA GATVGPGPVP APGRWVSSSV PASDPSDGQR RRQQQQQQQQ QQQQQPQQPQ VLSSEGGQLR HNPLDIQMLS RGLHEQIFGQ GGEMPGEAAV RRSVEHLQKH GLWGQPAVPL PDVELRLPPL YGDNLDQHFR LLAQKQSLPY LEAANLLLQA QLPPKPPAWA WAEGWTRYGP EGEAVPVAIP EERALVFDVE VCLAEGTCPT LAVAISPSAW YSWCSQRLVE ERYSWTSQLS PADLIPLEVP TGASSPTQRD WQEQLVVGHN VSFDRAHIRE QYLIQGSRMR FLDTMSMHMA ISGLSSFQRS LWIAAKQGKH KVQPPTKQGQ KSQRKARRGP AISSWDWLDI SSVNSLAEVH RLYVGGPPLE KEPRELFVKG TMKDIRENFQ DLMQYCAQDV WATHEVFQQQ LPLFLERCPH PVTLAGMLEM GVSYLPVNQN WERYLAEAQG TYEELQREMK KSLMDLANDA CQLLSGERYK EDPWLWDLEW DLQEFKQKKA KKVKKEPATA SKLPIEGAGA PGDPMDQEDL GPCSEEEEFQ QDVMARACLQ KLKGTTELLP KRPQHLPGHP GWYRKLCPRL DDPAWTPGPS LLSLQMRVTP KLMALTWDGF PLHYSERHGW GYLVPGRRDN LAKLPTGTTL ESAGVVCPYR AIESLYRKHC LEQGKQQLMP QEAGLAEEFL LTDNSAIWQT VEELDYLEVE AEAKMENLRA AVPGQPLALT ARGGPKDTQP SYHHGNGPYN DVDIPGCWFF KLPHKDGNSC NVGSPFAKDF LPKMEDGTLQ AGPGGASGPR ALEINKMISF WRNAHKRISS QMVVWLPRSA LPRAVIRHPD YDEEGLYGAI LPQVVTAGTI TRRAVEPTWL TASNARPDRV GSELKAMVQA PPGYTLVGAD VDSQELWIAA VLGDAHFAGM HGCTAFGWMT LQGRKSRGTD LHSKTATTVG ISREHAKIFN YGRIYGAGQP FAERLLMQFN HRLTQQEAAE KAQQMYAATK GLRWYRLSDE GEWLVRELNL PVDRTEGGWI SLQDLRKVQR ETARKSQWKK WEVVAERAWK GGTESEMFNK LESIATSDIP RTPVLGCCIS RALEPSAVQE EFMTSRVNWV VQSSAVDYLH LMLVAMKWLF EEFAIDGRFC ISIHDEVRYL VREEDRYRAA LALQITNLLT RCMFAYKLGL NDLPQSVAFF SAVDIDRCLR KEVTMDCKTP SNPTGMERRY GIPQGEALDI YQIIELTKGS LEKRSQPGP // ID DPOG2_HUMAN Reviewed; 485 AA. AC Q9UHN1; O00419; Q0IJ81; Q96GW2; Q9UK35; Q9UK94; DT 16-NOV-2001, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 1. DT 28-JAN-2026, entry version 201. DE RecName: Full=DNA polymerase subunit gamma-2; DE AltName: Full=DNA polymerase gamma accessory 55 kDa subunit; DE Short=p55 {ECO:0000303|PubMed:10608893}; DE AltName: Full=Mitochondrial DNA polymerase accessory subunit; DE AltName: Full=MtPolB; DE AltName: Full=PolG-beta; DE Flags: Precursor; GN Name=POLG2 {ECO:0000303|PubMed:30157269, ECO:0000312|HGNC:HGNC:9180}; GN Synonyms=MTPOLB; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Cerebellum; RX PubMed=10608893; DOI=10.1074/jbc.274.53.38197; RA Lim S.E., Longley M.J., Copeland W.C.; RT "The mitochondrial p55 accessory subunit of human DNA polymerase gamma RT enhances DNA binding, promotes processive DNA synthesis, and confers N- RT ethylmaleimide resistance."; RL J. Biol. Chem. 274:38197-38203(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT THR-169. RX PubMed=10666468; DOI=10.1093/nar/28.5.1237; RA Carrodeguas J.A., Bogenhagen D.F.; RT "Protein sequences conserved in prokaryotic aminoacyl-tRNA synthetases are RT important for the activity of the processivity factor of human RT mitochondrial DNA polymerase."; RL Nucleic Acids Res. 28:1237-1244(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=10677218; DOI=10.1021/bi992104w; RA Johnson A.A., Tsai Y.-C., Graves S.W., Johnson K.A.; RT "Human mitochondrial DNA polymerase holoenzyme: reconstitution and RT characterization."; RL Biochemistry 39:1702-1708(2000). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS THR-169 AND ALA-416. RC TISSUE=Cervix, and Ovary; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] OF 114-485. RX PubMed=9153213; DOI=10.1074/jbc.272.21.13640; RA Wang Y., Farr C.L., Kaguni L.S.; RT "Accessory subunit of mitochondrial DNA polymerase from Drosophila embryos. RT Cloning, molecular analysis, and association in the native enzyme."; RL J. Biol. Chem. 272:13640-13646(1997). RN [6] RP FUNCTION, AND SUBUNIT. RX PubMed=11477093; DOI=10.1074/jbc.m106045200; RA Johnson A.A., Johnson K.A.; RT "Fidelity of nucleotide incorporation by human mitochondrial DNA RT polymerase."; RL J. Biol. Chem. 276:38090-38096(2001). RN [7] RP FUNCTION, AND SUBUNIT. RX PubMed=11477094; DOI=10.1074/jbc.m106046200; RA Johnson A.A., Johnson K.A.; RT "Exonuclease proofreading by human mitochondrial DNA polymerase."; RL J. Biol. Chem. 276:38097-38107(2001). RN [8] RP FUNCTION, AND SUBUNIT. RX PubMed=11504725; DOI=10.1074/jbc.m105230200; RA Longley M.J., Nguyen D., Kunkel T.A., Copeland W.C.; RT "The fidelity of human DNA polymerase gamma with and without exonucleolytic RT proofreading and the p55 accessory subunit."; RL J. Biol. Chem. 276:38555-38562(2001). RN [9] RP FUNCTION, AND SUBUNIT. RX PubMed=15167897; DOI=10.1038/sj.emboj.7600257; RA Korhonen J.A., Pham X.H., Pellegrini M., Falkenberg M.; RT "Reconstitution of a minimal mtDNA replisome in vitro."; RL EMBO J. 23:2423-2429(2004). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-38, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [12] RP FUNCTION, AND CHARACTERIZATION OF VARIANT MTDPS16 TRP-182. RX PubMed=30157269; DOI=10.1371/journal.pone.0203198; RA Hoff K.E., DeBalsi K.L., Sanchez-Quintero M.J., Longley M.J., Hirano M., RA Naini A.B., Copeland W.C.; RT "Characterization of the human homozygous R182W POLG2 mutation in RT mitochondrial DNA depletion syndrome."; RL PLoS ONE 13:e0203198-e0203198(2018). RN [13] RP X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) OF 1-146 AND 181-485, FUNCTION, AND RP SUBUNIT. RX PubMed=19837034; DOI=10.1016/j.cell.2009.07.050; RA Lee Y.S., Kennedy W.D., Yin Y.W.; RT "Structural insight into processive human mitochondrial DNA synthesis and RT disease-related polymerase mutations."; RL Cell 139:312-324(2009). RN [14] RP X-RAY CRYSTALLOGRAPHY (3.30 ANGSTROMS) OF 26-485, FUNCTION, AND SUBUNIT. RX PubMed=26056153; DOI=10.15252/embj.201591520; RA Szymanski M.R., Kuznetsov V.B., Shumate C., Meng Q., Lee Y.S., Patel G., RA Patel S., Yin Y.W.; RT "Structural basis for processivity and antiviral drug toxicity in human RT mitochondrial DNA replicase."; RL EMBO J. 34:1959-1970(2015). RN [15] RP STRUCTURE BY ELECTRON MICROSCOPY (2.46 ANGSTROMS), FUNCTION, AND SUBUNIT. RX PubMed=37202477; DOI=10.1038/s41594-023-00980-2; RA Park J., Herrmann G.K., Mitchell P.G., Sherman M.B., Yin Y.W.; RT "Polgamma coordinates DNA synthesis and proofreading to ensure RT mitochondrial genome integrity."; RL Nat. Struct. Mol. Biol. 30:812-823(2023). RN [16] RP VARIANT PEOA4 GLU-451, AND CHARACTERIZATION OF VARIANT PEOA4 GLU-451. RX PubMed=16685652; DOI=10.1086/504303; RA Longley M.J., Clark S., Man C.Y.W., Hudson G., Durham S.E., Taylor R.W., RA Nightingale S., Turnbull D.M., Copeland W.C., Chinnery P.F.; RT "Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive RT external ophthalmoplegia."; RL Am. J. Hum. Genet. 78:1026-1034(2006). RN [17] RP VARIANT ALA-416, AND CHARACTERIZATION OF VARIANT ALA-416. RX PubMed=18195150; DOI=10.1001/archneurol.2007.9; RA Ferraris S., Clark S., Garelli E., Davidzon G., Moore S.A., Kardon R.H., RA Bienstock R.J., Longley M.J., Mancuso M., Gutierrez Rios P., Hirano M., RA Copeland W.C., DiMauro S.; RT "Progressive external ophthalmoplegia and vision and hearing loss in a RT patient with mutations in POLG2 and OPA1."; RL Arch. Neurol. 65:125-131(2008). RN [18] RP VARIANT MTDPS16 TRP-182, AND INVOLVEMENT IN MTDPS16. RX PubMed=27592148; DOI=10.1016/j.ejmg.2016.08.012; RA Varma H., Faust P.L., Iglesias A.D., Lagana S.M., Wou K., Hirano M., RA DiMauro S., Mansukani M.M., Hoff K.E., Nagy P.L., Copeland W.C., RA Naini A.B.; RT "Whole exome sequencing identifies a homozygous POLG2 missense variant in RT an infant with fulminant hepatic failure and mitochondrial DNA depletion."; RL Eur. J. Med. Genet. 59:540-545(2016). RN [19] RP VARIANT MTDPS16B TYR-433, INVOLVEMENT IN MTDPS16B, CHARACTERIZATION OF RP VARIANT MTDPS16B TYR-433, AND FUNCTION. RX PubMed=31778857; DOI=10.1016/j.ejmg.2019.103821; RA Dosekova P., Dubiel A., Karlowicz A., Zietkiewicz S., Rydzanicz M., RA Habalova V., Pienkowski V.M., Skirkova M., Han V., Mosejova A., RA Gdovinova Z., Kaliszewska M., Tonska K., Szymanski M.R., Skorvanek M., RA Ploski R.; RT "Whole exome sequencing identifies a homozygous POLG2 missense variant in RT an adult patient presenting with optic atrophy, movement disorders, RT premature ovarian failure and mitochondrial DNA depletion."; RL Eur. J. Med. Genet. 63:103821-103821(2020). CC -!- FUNCTION: Accessory subunit of DNA polymerase gamma solely responsible CC for replication of mitochondrial DNA (mtDNA). Acts as an allosteric CC regulator of the holoenzyme activities. Enhances the polymerase CC activity and the processivity of POLG by increasing its interactions CC with the DNA template. Suppresses POLG exonucleolytic proofreading CC especially toward homopolymeric templates bearing mismatched termini. CC Binds to single-stranded DNA. {ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:11504725, CC ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:19837034, CC ECO:0000269|PubMed:26056153, ECO:0000269|PubMed:30157269, CC ECO:0000269|PubMed:31778857, ECO:0000269|PubMed:37202477}. CC -!- SUBUNIT: Heterotrimer composed of a catalytic subunit and a homodimer CC of accessory subunits (POLG:POLG2). {ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:11504725, CC ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:19837034, CC ECO:0000269|PubMed:26056153, ECO:0000269|PubMed:37202477}. CC -!- INTERACTION: CC Q9UHN1; P54098: POLG; NbExp=15; IntAct=EBI-852642, EBI-852624; CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250|UniProtKB:P54098}. CC Mitochondrion matrix, mitochondrion nucleoid CC {ECO:0000250|UniProtKB:P54098}. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 4 (PEOA4) [MIM:610131]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:16685652}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 16, hepatic type CC (MTDPS16) [MIM:618528]: An autosomal recessive disorder characterized CC by poor feeding, difficulty breathing, abdominal distention, an CC abnormal carnitine profile, metabolic acidosis and hepatic failure in CC the neonatal period. Severe mtDNA depletion is observed in liver and CC muscle biopsies. {ECO:0000269|PubMed:27592148, CC ECO:0000269|PubMed:30157269}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 16B, neuroophthalmic type CC (MTDPS16B) [MIM:619425]: An autosomal recessive disorder characterized CC by childhood onset of progressive neuroophthalmic manifestations with CC optic atrophy, mixed polyneuropathy, spinal and cerebellar ataxia, and CC generalized chorea associated with mtDNA depletion. CC {ECO:0000269|PubMed:31778857}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF142992; AAD50382.1; -; mRNA. DR EMBL; AF177201; AAD56640.1; -; mRNA. DR EMBL; AF184344; AAD56542.1; -; mRNA. DR EMBL; BC000913; AAH00913.2; -; mRNA. DR EMBL; BC009194; AAH09194.1; -; mRNA. DR EMBL; U94703; AAC51321.1; -; mRNA. DR CCDS; CCDS32706.1; -. DR RefSeq; NP_009146.2; NM_007215.4. DR PDB; 2G4C; X-ray; 3.15 A; A/B/C/D=26-485. DR PDB; 3IKL; X-ray; 3.10 A; A/B=1-146, A/B=181-485. DR PDB; 3IKM; X-ray; 3.24 A; B/C/E/F=59-485. DR PDB; 4ZTU; X-ray; 3.30 A; B/C=26-485. DR PDB; 4ZTZ; X-ray; 3.44 A; B/C=26-485. DR PDB; 5C51; X-ray; 3.43 A; B/C=1-485. DR PDB; 5C52; X-ray; 3.64 A; B/C=1-485. DR PDB; 5C53; X-ray; 3.57 A; B/C=1-485. DR PDB; 8D33; EM; 2.46 A; B/C=1-485. DR PDB; 8D37; EM; 2.65 A; B/C=1-485. DR PDB; 8D3R; EM; 3.04 A; B/C=1-485. DR PDB; 8D42; EM; 2.91 A; B/C=1-485. DR PDB; 8G5I; EM; 2.75 A; B/C=1-485. DR PDB; 8G5J; EM; 2.63 A; B/C=1-485. DR PDB; 8G5K; EM; 2.90 A; B/C=1-485. DR PDB; 8G5L; EM; 3.00 A; B/C=1-485. DR PDB; 8G5M; EM; 2.58 A; B/C=1-485. DR PDB; 8G5N; EM; 2.73 A; B/C=1-485. DR PDB; 8G5O; EM; 2.61 A; B/C=1-485. DR PDB; 8G5P; EM; 2.78 A; B/C=1-485. DR PDB; 8T7E; EM; 3.08 A; B/C=1-485. DR PDB; 8UDK; X-ray; 3.43 A; B/C=1-485. DR PDB; 8UDL; EM; 2.37 A; B/C=1-485. DR PDB; 8V54; EM; 4.10 A; B/C=26-485. DR PDB; 8V55; EM; 4.20 A; B/C=26-485. DR PDB; 8V5R; EM; 3.00 A; B/C=26-485. DR PDB; 9GGB; EM; 2.63 A; B/C=25-485. DR PDB; 9GGC; EM; 2.39 A; B/C=25-485. DR PDB; 9GGD; EM; 2.67 A; B/C=25-485. DR PDB; 9GGE; EM; 2.69 A; B/C=25-485. DR PDB; 9GGF; EM; 2.65 A; B/C=25-485. DR PDB; 9IBX; EM; 2.54 A; B/C=25-485. DR PDB; 9IBZ; EM; 3.08 A; B/C=25-485. DR PDB; 9IC0; EM; 3.24 A; B/C=25-485. DR PDBsum; 2G4C; -. DR PDBsum; 3IKL; -. DR PDBsum; 3IKM; -. DR PDBsum; 4ZTU; -. DR PDBsum; 4ZTZ; -. DR PDBsum; 5C51; -. DR PDBsum; 5C52; -. DR PDBsum; 5C53; -. DR PDBsum; 8D33; -. DR PDBsum; 8D37; -. DR PDBsum; 8D3R; -. DR PDBsum; 8D42; -. DR PDBsum; 8G5I; -. DR PDBsum; 8G5J; -. DR PDBsum; 8G5K; -. DR PDBsum; 8G5L; -. DR PDBsum; 8G5M; -. DR PDBsum; 8G5N; -. DR PDBsum; 8G5O; -. DR PDBsum; 8G5P; -. DR PDBsum; 8T7E; -. DR PDBsum; 8UDK; -. DR PDBsum; 8UDL; -. DR PDBsum; 8V54; -. DR PDBsum; 8V55; -. DR PDBsum; 8V5R; -. DR PDBsum; 9GGB; -. DR PDBsum; 9GGC; -. DR PDBsum; 9GGD; -. DR PDBsum; 9GGE; -. DR PDBsum; 9GGF; -. DR PDBsum; 9IBX; -. DR PDBsum; 9IBZ; -. DR PDBsum; 9IC0; -. DR AlphaFoldDB; Q9UHN1; -. DR EMDB; EMD-27154; -. DR EMDB; EMD-27155; -. DR EMDB; EMD-27163; -. DR EMDB; EMD-27172; -. DR EMDB; EMD-29745; -. DR EMDB; EMD-29746; -. DR EMDB; EMD-29747; -. DR EMDB; EMD-29748; -. DR EMDB; EMD-29749; -. DR EMDB; EMD-29750; -. DR EMDB; EMD-29751; -. DR EMDB; EMD-29752; -. DR EMDB; EMD-41091; -. DR EMDB; EMD-42150; -. DR EMDB; EMD-42842; -. DR EMDB; EMD-42979; -. DR EMDB; EMD-42980; -. DR EMDB; EMD-42984; -. DR EMDB; EMD-51326; -. DR EMDB; EMD-51327; -. DR EMDB; EMD-51328; -. DR EMDB; EMD-51329; -. DR EMDB; EMD-51330; -. DR EMDB; EMD-52815; -. DR EMDB; EMD-52819; -. DR EMDB; EMD-52823; -. DR SMR; Q9UHN1; -. DR BioGRID; 116398; 39. DR ComplexPortal; CPX-2093; Mitochondrial DNA polymerase gamma complex. DR FunCoup; Q9UHN1; 851. DR IntAct; Q9UHN1; 37. DR MINT; Q9UHN1; -. DR STRING; 9606.ENSP00000442563; -. DR ChEMBL; CHEMBL3430903; -. DR DrugBank; DB12151; Brincidofovir. DR iPTMnet; Q9UHN1; -. DR PhosphoSitePlus; Q9UHN1; -. DR BioMuta; POLG2; -. DR DMDM; 17367139; -. DR jPOST; Q9UHN1; -. DR MassIVE; Q9UHN1; -. DR PaxDb; 9606-ENSP00000442563; -. DR PeptideAtlas; Q9UHN1; -. DR ProteomicsDB; 84382; -. DR Pumba; Q9UHN1; -. DR Antibodypedia; 50586; 171 antibodies from 29 providers. DR DNASU; 11232; -. DR Ensembl; ENST00000539111.7; ENSP00000442563.2; ENSG00000256525.9. DR GeneID; 11232; -. DR KEGG; hsa:11232; -. DR MANE-Select; ENST00000539111.7; ENSP00000442563.2; NM_007215.4; NP_009146.2. DR UCSC; uc002jei.4; human. DR AGR; HGNC:9180; -. DR ClinPGx; PA33501; -. DR CTD; 11232; -. DR DisGeNET; 11232; -. DR GeneCards; POLG2; -. DR HGNC; HGNC:9180; POLG2. DR HPA; ENSG00000256525; Low tissue specificity. DR MalaCards; POLG2; -. DR MIM; 604983; gene. DR MIM; 610131; phenotype. DR MIM; 618528; phenotype. DR MIM; 619425; phenotype. DR OpenTargets; ENSG00000256525; -. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR VEuPathDB; HostDB:ENSG00000256525; -. DR eggNOG; KOG2298; Eukaryota. DR GeneTree; ENSGT00940000153759; -. DR HOGENOM; CLU_055833_0_0_1; -. DR InParanoid; Q9UHN1; -. DR OMA; WGQEVLE; -. DR OrthoDB; 57698at2759; -. DR PAN-GO; Q9UHN1; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q9UHN1; -. DR BRENDA; 2.7.7.7; 2681. DR PathwayCommons; Q9UHN1; -. DR Reactome; R-HSA-2151201; Transcriptional activation of mitochondrial biogenesis. DR Reactome; R-HSA-9913635; Strand-asynchronous mitochondrial DNA replication. DR SignaLink; Q9UHN1; -. DR SIGNOR; Q9UHN1; -. DR Agora; ENSG00000256525; -. DR BioGRID-ORCS; 11232; 326 hits in 1164 CRISPR screens. DR ChiTaRS; POLG2; human. DR EvolutionaryTrace; Q9UHN1; -. DR GeneWiki; POLG2; -. DR GenomeRNAi; 11232; -. DR Pharos; Q9UHN1; Tbio. DR PRO; PR:Q9UHN1; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; Q9UHN1; protein. DR Bgee; ENSG00000256525; Expressed in secondary oocyte and 177 other cell types or tissues. DR ExpressionAtlas; Q9UHN1; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005760; C:gamma DNA polymerase complex; IDA:UniProtKB. DR GO; GO:0005759; C:mitochondrial matrix; IDA:ComplexPortal. DR GO; GO:0042645; C:mitochondrial nucleoid; IDA:BHF-UCL. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0070182; F:DNA polymerase binding; IPI:UniProtKB. DR GO; GO:0030337; F:DNA polymerase processivity factor activity; IDA:UniProtKB. DR GO; GO:0003887; F:DNA-directed DNA polymerase activity; IEA:Ensembl. DR GO; GO:0003690; F:double-stranded DNA binding; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl. DR GO; GO:0006261; P:DNA-templated DNA replication; IDA:UniProtKB. DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl. DR GO; GO:0006264; P:mitochondrial DNA replication; IDA:FlyBase. DR GO; GO:0007005; P:mitochondrion organization; IEA:Ensembl. DR GO; GO:1900264; P:positive regulation of DNA-directed DNA polymerase activity; IDA:UniProtKB. DR CDD; cd02426; Pol_gamma_b_Cterm; 1. DR FunFam; 3.40.50.800:FF:000014; Putative dna polymerase subunit gamma-2 mitochondrial; 1. DR Gene3D; 3.40.50.800; Anticodon-binding domain; 1. DR Gene3D; 3.30.930.10; Bira Bifunctional Protein, Domain 2; 1. DR InterPro; IPR045864; aa-tRNA-synth_II/BPL/LPL. DR InterPro; IPR004154; Anticodon-bd. DR InterPro; IPR036621; Anticodon-bd_dom_sf. DR InterPro; IPR027031; Gly-tRNA_synthase/POLG2. DR InterPro; IPR042064; POLG2_C. DR PANTHER; PTHR10745:SF8; DNA POLYMERASE SUBUNIT GAMMA-2, MITOCHONDRIAL; 1. DR PANTHER; PTHR10745; GLYCYL-TRNA SYNTHETASE/DNA POLYMERASE SUBUNIT GAMMA-2; 1. DR Pfam; PF03129; HGTP_anticodon; 1. DR SUPFAM; SSF52954; Class II aaRS ABD-related; 1. DR SUPFAM; SSF55681; Class II aaRS and biotin synthetases; 1. PE 1: Evidence at protein level; KW 3D-structure; Disease variant; DNA replication; DNA-binding; Mitochondrion; KW Mitochondrion nucleoid; Phosphoprotein; Primary mitochondrial disease; KW Progressive external ophthalmoplegia; Proteomics identification; KW Reference proteome; Transit peptide. FT TRANSIT 1..? FT /note="Mitochondrion" FT /evidence="ECO:0000255" FT CHAIN ?..485 FT /note="DNA polymerase subunit gamma-2" FT /id="PRO_0000007314" FT REGION 28..65 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 46..58 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 38 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT VARIANT 169 FT /note="A -> T (in dbSNP:rs1427463)" FT /evidence="ECO:0000269|PubMed:10666468, FT ECO:0000269|PubMed:15489334" FT /id="VAR_032028" FT VARIANT 182 FT /note="R -> W (in MTDPS16; decreased function in FT mitochondrial DNA replication; decreased protein stability; FT no effect on DNA binding; dbSNP:rs886037843)" FT /evidence="ECO:0000269|PubMed:27592148, FT ECO:0000269|PubMed:30157269" FT /id="VAR_078773" FT VARIANT 416 FT /note="G -> A (no functional deficit; dbSNP:rs17850455)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:18195150" FT /id="VAR_032029" FT VARIANT 433 FT /note="D -> Y (in MTDPS16B; decreased DNA polymerase FT processivity factor activity; results in decreased FT stability; affects the secondary structure as shown by FT circular dichroism spectroscopy; dbSNP:rs2144120492)" FT /evidence="ECO:0000269|PubMed:31778857" FT /id="VAR_086017" FT VARIANT 451 FT /note="G -> E (in PEOA4; affects stimulation of the FT catalytic subunit; dbSNP:rs104894632)" FT /evidence="ECO:0000269|PubMed:16685652" FT /id="VAR_029364" FT CONFLICT 114..124 FT /note="WWTSVVVFREQ -> MVDLGGGVHGA (in Ref. 5; AAC51321)" FT /evidence="ECO:0000305" FT CONFLICT 122 FT /note="R -> T (in Ref. 3; AAD56542)" FT /evidence="ECO:0000305" FT CONFLICT 136 FT /note="G -> S (in Ref. 3; AAD56542 and 5; AAC51321)" FT /evidence="ECO:0000305" FT CONFLICT 287..292 FT /note="NKLYYN -> TNFTTI (in Ref. 5; AAC51321)" FT /evidence="ECO:0000305" FT HELIX 65..75 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 78..80 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 83..85 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 88..93 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 101..118 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 119..121 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 125..127 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 132..134 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 135..137 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 138..141 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 144..146 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 152..156 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 157..159 FT /evidence="ECO:0007829|PDB:2G4C" FT HELIX 165..169 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 170..176 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 179..181 FT /evidence="ECO:0007829|PDB:8V5R" FT HELIX 186..190 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 193..196 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 197..200 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 206..218 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 224..226 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 230..243 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 245..247 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 248..266 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 270..272 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 273..279 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 281..284 FT /evidence="ECO:0007829|PDB:3IKL" FT STRAND 285..293 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 296..308 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 309..314 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 319..321 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 324..326 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 329..331 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 334..341 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 342..353 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 359..361 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 362..365 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 376..378 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 379..381 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 383..387 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 392..408 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 413..415 FT /evidence="ECO:0007829|PDB:8D33" FT HELIX 416..418 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 419..421 FT /evidence="ECO:0007829|PDB:3IKL" FT HELIX 425..434 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 438..443 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 445..450 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 452..457 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 458..460 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 463..467 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 468..470 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 471..482 FT /evidence="ECO:0007829|PDB:8UDL" SQ SEQUENCE 485 AA; 54911 MW; B99734BFEA249192 CRC64; MRSRVAVRAC HKVCRCLLSG FGGRVDAGQP ELLTERSSPK GGHVKSHAEL EGNGEHPEAP GSGEGSEALL EICQRRHFLS GSKQQLSRDS LLSGCHPGFG PLGVELRKNL AAEWWTSVVV FREQVFPVDA LHHKPGPLLP GDSAFRLVSA ETLREILQDK ELSKEQLVAF LENVLKTSGK LRENLLHGAL EHYVNCLDLV NKRLPYGLAQ IGVCFHPVFD TKQIRNGVKS IGEKTEASLV WFTPPRTSNQ WLDFWLRHRL QWWRKFAMSP SNFSSSDCQD EEGRKGNKLY YNFPWGKELI ETLWNLGDHE LLHMYPGNVS KLHGRDGRKN VVPCVLSVNG DLDRGMLAYL YDSFQLTENS FTRKKNLHRK VLKLHPCLAP IKVALDVGRG PTLELRQVCQ GLFNELLENG ISVWPGYLET MQSSLEQLYS KYDEMSILFT VLVTETTLEN GLIHLRSRDT TMKEMMHISK LKDFLIKYIS SAKNV // ID PEO1_HUMAN Reviewed; 684 AA. AC Q96RR1; B2CQL2; Q6MZX2; Q6PJP5; Q96RR0; DT 25-OCT-2005, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 28-JAN-2026, entry version 193. DE RecName: Full=Twinkle mtDNA helicase {ECO:0000312|HGNC:HGNC:1160}; DE EC=5.6.2.3 {ECO:0000269|PubMed:12975372, ECO:0000269|PubMed:17324440, ECO:0000269|PubMed:18039713, ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949, ECO:0000269|PubMed:27226550}; DE AltName: Full=Progressive external ophthalmoplegia 1 protein; DE AltName: Full=T7 gp4-like protein with intramitochondrial nucleoid localization; DE AltName: Full=T7-like mitochondrial DNA helicase; DE AltName: Full=Twinkle protein, mitochondrial {ECO:0000305}; DE Flags: Precursor; GN Name=TWNK {ECO:0000312|HGNC:HGNC:1160}; Synonyms=C10orf2, PEO1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY, RP SUBCELLULAR LOCATION, VARIANT ILE-368, AND VARIANTS PEOA3 LEU-315; PRO-354; RP THR-359; THR-367; PRO-369; GLN-374; PRO-381; CYS-474 AND PRO-475. RX PubMed=11431692; DOI=10.1038/90058; RA Spelbrink J.N., Li F.-Y., Tiranti V., Nikali K., Yuan Q.-P., Tariq M., RA Wanrooij S., Garrido N., Comi G., Morandi L., Santoro L., Toscano A., RA Fabrizi G.-M., Somer H., Croxen R., Beeson D., Poulton J., Suomalainen A., RA Jacobs H.T., Zeviani M., Larsson C.; RT "Human mitochondrial DNA deletions associated with mutations in the gene RT for Twinkle, a phage T7 gene 4-like protein localized in mitochondria."; RL Nat. Genet. 28:223-231(2001). RN [2] RP ERRATUM OF PUBMED:11431692. RA Spelbrink J.N., Li F.-Y., Tiranti V., Nikali K., Yuan Q.-P., Tariq M., RA Wanrooij S., Garrido N., Comi G., Morandi L., Santoro L., Toscano A., RA Fabrizi G.-M., Somer H., Croxen R., Beeson D., Poulton J., Suomalainen A., RA Jacobs H.T., Zeviani M., Larsson C.; RL Nat. Genet. 29:100-100(2001). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Fetal brain; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-348; ILE-368 AND RP LYS-634. RG NIEHS SNPs program; RL Submitted (MAR-2008) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 132-582 (ISOFORM 2). RC TISSUE=Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP FUNCTION (ISOFORM 1), AND CATALYTIC ACTIVITY (ISOFORM 1). RX PubMed=12975372; DOI=10.1074/jbc.m306981200; RA Korhonen J.A., Gaspari M., Falkenberg M.; RT "TWINKLE has 5' -> 3' DNA helicase activity and is specifically stimulated RT by mitochondrial single-stranded DNA-binding protein."; RL J. Biol. Chem. 278:48627-48632(2003). RN [9] RP FUNCTION (ISOFORM 1), AND INTERACTION WITH POLG (ISOFORM 1). RX PubMed=15167897; DOI=10.1038/sj.emboj.7600257; RA Korhonen J.A., Pham X.H., Pellegrini M., Falkenberg M.; RT "Reconstitution of a minimal mtDNA replisome in vitro."; RL EMBO J. 23:2423-2429(2004). RN [10] RP TISSUE SPECIFICITY, AND COREGULATION WITH MRPL43. RX PubMed=15509589; DOI=10.1093/hmg/ddh342; RA Tyynismaa H., Sembongi H., Bokori-Brown M., Granycome C., Ashley N., RA Poulton J., Jalanko A., Spelbrink J.N., Holt I.J., Suomalainen A.; RT "Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA RT copy number."; RL Hum. Mol. Genet. 13:3219-3227(2004). RN [11] RP INTERACTION WITH LONP1. RX PubMed=14739292; DOI=10.1074/jbc.m309642200; RA Liu T., Lu B., Lee I., Ondrovicova G., Kutejova E., Suzuki C.K.; RT "DNA and RNA binding by the mitochondrial lon protease is regulated by RT nucleotide and protein substrate."; RL J. Biol. Chem. 279:13902-13910(2004). RN [12] RP POSSIBLE MECHANISM OF DELETION FORMATION. RX PubMed=15181170; DOI=10.1093/nar/gkh634; RA Wanrooij S., Luoma P., van Goethem G., van Broeckhoven C., Suomalainen A., RA Spelbrink J.N.; RT "Twinkle and POLG defects enhance age-dependent accumulation of mutations RT in the control region of mtDNA."; RL Nucleic Acids Res. 32:3053-3064(2004). RN [13] RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), AND SUBUNIT (ISOFORM RP 1). RX PubMed=17324440; DOI=10.1016/j.jmb.2007.01.079; RA Ziebarth T.D., Farr C.L., Kaguni L.S.; RT "Modular architecture of the hexameric human mitochondrial DNA helicase."; RL J. Mol. Biol. 367:1382-1391(2007). RN [14] RP FUNCTION (ISOFORMS 1 AND 2), CATALYTIC ACTIVITY (ISOFORM 1), SUBUNIT RP (ISOFORMS 1 AND 2), AND DOMAIN. RX PubMed=18039713; DOI=10.1093/nar/gkm1025; RA Farge G., Holmlund T., Khvorostova J., Rofougaran R., Hofer A., RA Falkenberg M.; RT "The N-terminal domain of TWINKLE contributes to single-stranded DNA RT binding and DNA helicase activities."; RL Nucleic Acids Res. 36:393-403(2008). RN [15] RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), SUBUNIT (ISOFORM 1), RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS LEU-315; GLU-319; RP THR-359; PRO-369; GLN-374 AND CYS-474. RX PubMed=18971204; DOI=10.1093/hmg/ddn359; RA Goffart S., Cooper H.M., Tyynismaa H., Wanrooij S., Suomalainen A., RA Spelbrink J.N.; RT "Twinkle mutations associated with autosomal dominant progressive external RT ophthalmoplegia lead to impaired helicase function and in vivo mtDNA RT replication stalling."; RL Hum. Mol. Genet. 18:328-340(2009). RN [16] RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), ACTIVITY REGULATION RP (ISOFORM 1), BIOPHYSICOCHEMICAL PROPERTIES (ISOFORM 1), SUBUNIT (ISOFORM RP 1), AND MUTAGENESIS OF LYS-421. RX PubMed=22383523; DOI=10.1074/jbc.m111.309468; RA Sen D., Nandakumar D., Tang G.Q., Patel S.S.; RT "Human mitochondrial DNA helicase TWINKLE is both an unwinding and RT annealing helicase."; RL J. Biol. Chem. 287:14545-14556(2012). RN [17] RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), AND SUBUNIT (ISOFORM RP 1). RX PubMed=25824949; DOI=10.1093/nar/gkv189; RA Fernandez-Millan P., Lazaro M., Cansiz-Arda S., Gerhold J.M., Rajala N., RA Schmitz C.A., Silva-Espina C., Gil D., Bernado P., Valle M., RA Spelbrink J.N., Sola M.; RT "The hexameric structure of the human mitochondrial replicative helicase RT Twinkle."; RL Nucleic Acids Res. 43:4284-4295(2015). RN [18] RP FUNCTION (ISOFORM 1). RX PubMed=26887820; DOI=10.1093/nar/gkw098; RA Sen D., Patel G., Patel S.S.; RT "Homologous DNA strand exchange activity of the human mitochondrial DNA RT helicase TWINKLE."; RL Nucleic Acids Res. 44:4200-4210(2016). RN [19] RP FUNCTION (ISOFORM 1), AND CATALYTIC ACTIVITY (ISOFORM 1). RX PubMed=27226550; DOI=10.1074/jbc.m115.712026; RA Khan I., Crouch J.D., Bharti S.K., Sommers J.A., Carney S.M., RA Yakubovskaya E., Garcia-Diaz M., Trakselis M.A., Brosh R.M. Jr.; RT "Biochemical Characterization of the Human Mitochondrial Replicative RT Twinkle Helicase: SUBSTRATE SPECIFICITY, DNA BRANCH MIGRATION, AND ABILITY RT TO OVERCOME BLOCKADES TO DNA UNWINDING."; RL J. Biol. Chem. 291:14324-14339(2016). RN [20] RP SUBUNIT (ISOFORM 1), AND CHARACTERIZATION OF PEOA3 LEU-314; GLN-334; RP LEU-335; PRO-369 AND PRO-381. RX PubMed=30496414; DOI=10.1093/hmg/ddy415; RA Peter B., Farge G., Pardo-Hernandez C., Taangefjord S., Falkenberg M.; RT "Structural basis for adPEO-causing mutations in the mitochondrial TWINKLE RT helicase."; RL Hum. Mol. Genet. 28:1090-1099(2019). RN [21] RP SUBCELLULAR LOCATION. RX PubMed=34950192; DOI=10.3389/fgene.2021.790521; RA So M., Stiban J., Ciesielski G.L., Hovde S.L., Kaguni L.S.; RT "Implications of Membrane Binding by the Fe-S Cluster-Containing N-Terminal RT Domain in the Drosophila Mitochondrial Replicative DNA Helicase."; RL Front. Genet. 12:790521-790521(2021). RN [22] {ECO:0007744|PDB:7T8B, ECO:0007744|PDB:7T8C} RP STRUCTURE BY ELECTRON MICROSCOPY (3.8 ANGSTROMS) OF 1-684 OF VARIANT RP LEU-315, CATALYTIC ACTIVITY, SUBUNIT, AND CHARACTERIZATION OF VARIANT RP LEU-315. RX PubMed=35914129; DOI=10.1073/pnas.2207459119; RA Riccio A.A., Bouvette J., Perera L., Longley M.J., Krahn J.M., RA Williams J.G., Dutcher R., Borgnia M.J., Copeland W.C.; RT "Structural insight and characterization of human Twinkle helicase in RT mitochondrial disease."; RL Proc. Natl. Acad. Sci. U.S.A. 119:e2207459119-e2207459119(2022). RN [23] RP VARIANTS PEOA3 LEU-335 AND TYR-369. RX PubMed=12163192; DOI=10.1016/s0022-510x(02)00190-9; RA Lewis S., Hutchison W., Thyagarajan D., Dahl H.-H.M.; RT "Clinical and molecular features of adPEO due to mutations in the Twinkle RT gene."; RL J. Neurol. Sci. 201:39-44(2002). RN [24] RP VARIANT ILE-368. RX PubMed=12557300; DOI=10.1002/ana.10430; RA Arenas J., Briem E., Dahl H.-H.M., Hutchison W., Lewis S., Martin M.A., RA Spelbrink H., Tiranti V., Jacobs H., Zeviani M.; RT "The V368I mutation in Twinkle does not segregate with AdPEO."; RL Ann. Neurol. 53:278-278(2003). RN [25] RP VARIANT PEO GLN-334. RX PubMed=12872260; DOI=10.1002/humu.10246; RA Van Goethem G., Loefgren A., Dermaut B., Ceuterick C., Martin J.-J., RA Van Broeckhoven C.; RT "Digenic progressive external ophthalmoplegia in a sporadic patient: RT recessive mutations in POLG and C10orf2/Twinkle."; RL Hum. Mutat. 22:175-176(2003). RN [26] RP VARIANTS PEO TRP-303 AND GLN-334. RX PubMed=12707443; DOI=10.1212/01.wnl.0000056088.09408.3c; RA Agostino A., Valletta L., Chinnery P.F., Ferrari G., Carrara F., RA Taylor R.W., Schaefer A.M., Turnbull D.M., Tiranti V., Zeviani M.; RT "Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external RT ophthalmoplegia (PEO)."; RL Neurology 60:1354-1356(2003). RN [27] RP VARIANT PEOA3 THR-319. RX PubMed=12921794; DOI=10.1016/s0960-8966(03)00071-3; RA Deschauer M., Kiefer R., Blakely E.L., He L., Zierz S., Turnbull D.M., RA Taylor R.W.; RT "A novel Twinkle gene mutation in autosomal dominant progressive external RT ophthalmoplegia."; RL Neuromuscul. Disord. 13:568-572(2003). RN [28] RP VARIANT MTDPS7 CYS-508. RX PubMed=16135556; DOI=10.1093/hmg/ddi328; RA Nikali K., Suomalainen A., Saharinen J., Kuokkanen M., Spelbrink J.N., RA Loennqvist T., Peltonen L.; RT "Infantile onset spinocerebellar ataxia is caused by recessive mutations in RT mitochondrial proteins Twinkle and Twinky."; RL Hum. Mol. Genet. 14:2981-2990(2005). RN [29] RP VARIANT PEOA3 GLU-319. RX PubMed=15668446; DOI=10.1212/01.wnl.0000149767.51152.83; RA Hudson G., Deschauer M., Busse K., Zierz S., Chinnery P.F.; RT "Sensory ataxic neuropathy due to a novel C10Orf2 mutation with probable RT germline mosaicism."; RL Neurology 64:371-373(2005). RN [30] RP VARIANT PEOA3 GLN-374, AND VARIANT ILE-368. RX PubMed=16639411; DOI=10.1038/sj.ejhg.5201627; RA Naiemi M., Bannwarth S., Procaccio V., Pouget J., Desnuelle C., RA Pellissier J.-F., Roetig A., Munnich A., Calvas P., Richelme C., RA Jonveaux P., Castelnovo G., Simon M., Clanet M., Wallace D., RA Paquis-Flucklinger V.; RT "Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple RT deletions or depletion of mitochondrial DNA by a dHPLC-based assay."; RL Eur. J. Hum. Genet. 14:917-922(2006). RN [31] RP VARIANT MTDPS7 ILE-457, AND CHARACTERIZATION OF VARIANT MTDPS7 ILE-457. RX PubMed=17722119; DOI=10.1002/ana.21207; RA Sarzi E., Goffart S., Serre V., Chretien D., Slama A., Munnich A., RA Spelbrink J.N., Roetig A.; RT "Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA RT depletion."; RL Ann. Neurol. 62:579-587(2007). RN [32] RP VARIANTS MTDPS7 THR-318 AND CYS-508. RX PubMed=17921179; DOI=10.1093/brain/awm242; RA Hakonen A.H., Isohanni P., Paetau A., Herva R., Suomalainen A., RA Lonnqvist T.; RT "Recessive Twinkle mutations in early onset encephalopathy with mtDNA RT depletion."; RL Brain 130:3032-3040(2007). RN [33] RP VARIANT PEOA3 PRO-357. RX PubMed=17614277; DOI=10.1016/j.nmd.2007.05.006; RA Rivera H., Blazquez A., Carretero J., Alvarez-Cermeno J.C., Campos Y., RA Cabello A., Gonzalez-Vioque E., Borstein B., Garesse R., Arenas J., RA Martin M.A.; RT "Mild ocular myopathy associated with a novel mutation in mitochondrial RT twinkle helicase."; RL Neuromuscul. Disord. 17:677-680(2007). RN [34] RP VARIANTS PEOA3 TRP-303; SER-315; PRO-334; ASN-426; SER-474; ILE-478 AND RP LYS-479. RX PubMed=18575922; DOI=10.1007/s00415-008-0926-3; RA Virgilio R., Ronchi D., Hadjigeorgiou G.M., Bordoni A., Saladino F., RA Moggio M., Adobbati L., Kafetsouli D., Tsironi E., Previtali S., RA Papadimitriou A., Bresolin N., Comi G.P.; RT "Novel Twinkle (PEO1) gene mutations in Mendelian progressive external RT ophthalmoplegia."; RL J. Neurol. 255:1384-1391(2008). RN [35] RP VARIANT PEOA3 LEU-370. RX PubMed=18396044; DOI=10.1016/j.nmd.2007.10.007; RA Jeppesen T.D., Schwartz M., Colding-Jorgensen E., Krag T., Hauerslev S., RA Vissing J.; RT "Phenotype and clinical course in a family with a new de novo Twinkle gene RT mutation."; RL Neuromuscul. Disord. 18:306-309(2008). RN [36] RP VARIANT PEOA3 GLN-303. RX PubMed=19353676; DOI=10.1002/ajmg.a.32731; RA Van Hove J.L., Cunningham V., Rice C., Ringel S.P., Zhang Q., Chou P.C., RA Truong C.K., Wong L.J.; RT "Finding twinkle in the eyes of a 71-year-old lady: a case report and RT review of the genotypic and phenotypic spectrum of TWINKLE-related dominant RT disease."; RL Am. J. Med. Genet. A 149:861-867(2009). RN [37] RP VARIANT PEOA3 TRP-303. RX PubMed=19428252; DOI=10.1016/j.nmd.2009.04.008; RA Negro R., Zoccolella S., Dell'aglio R., Amati A., Artuso L., Bisceglia L., RA Lavolpe V., Papa S., Serlenga L., Petruzzella V.; RT "Molecular analysis in a family presenting with a mild form of late-onset RT autosomal dominant chronic progressive external ophthalmoplegia."; RL Neuromuscul. Disord. 19:423-426(2009). RN [38] RP VARIANT MTDPS7 GLY-360. RX PubMed=19853444; DOI=10.1016/j.nmd.2009.10.002; RA Bohlega S., Van Goethem G., Al Semari A., Lofgren A., Al Hamed M., RA Van Broeckhoven C., Kambouris M.; RT "Novel Twinkle gene mutation in autosomal dominant progressive external RT ophthalmoplegia and multisystem failure."; RL Neuromuscul. Disord. 19:845-848(2009). RN [39] RP VARIANTS PEOA3 GLN-303; TRP-303; GLN-334; PRO-354; PRO-357; THR-359; RP PRO-362; LEU-363; CYS-370; GLN-374; PRO-381; HIS-458; PRO-460; ASP-475 AND RP LYS-479. RX PubMed=20479361; DOI=10.1212/wnl.0b013e3181df099f; RA Fratter C., Gorman G.S., Stewart J.D., Buddles M., Smith C., Evans J., RA Seller A., Poulton J., Roberts M., Hanna M.G., Rahman S., Omer S.E., RA Klopstock T., Schoser B., Kornblum C., Czermin B., Lecky B., Blakely E.L., RA Craig K., Chinnery P.F., Turnbull D.M., Horvath R., Taylor R.W.; RT "The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)- RT linked adPEO."; RL Neurology 74:1619-1626(2010). RN [40] RP VARIANT PEOA3 GLN-374. RX PubMed=20880070; DOI=10.1111/j.1468-1331.2010.03171.x; RA Martin-Negrier M.L., Sole G., Jardel C., Vital C., Ferrer X., Vital A.; RT "TWINKLE gene mutation: report of a French family with an autosomal RT dominant progressive external ophthalmoplegia and literature review."; RL Eur. J. Neurol. 18:436-441(2011). RN [41] RP VARIANT MTDPS7 VAL-456. RX PubMed=22353293; DOI=10.1016/j.pediatrneurol.2011.12.006; RA Dundar H., Ozgul R.K., Yalnizoglu D., Erdem S., Oguz K.K., Tuncel D., RA Temucin C.M., Dursun A.; RT "Identification of a novel Twinkle mutation in a family with infantile RT onset spinocerebellar ataxia by whole exome sequencing."; RL Pediatr. Neurol. 46:172-177(2012). RN [42] RP INVOLVEMENT IN PRLTS5, AND VARIANTS PRLTS5 HIS-391; GLY-441; ILE-507 AND RP SER-585. RX PubMed=25355836; DOI=10.1212/wnl.0000000000001036; RA Morino H., Pierce S.B., Matsuda Y., Walsh T., Ohsawa R., Newby M., RA Hiraki-Kamon K., Kuramochi M., Lee M.K., Klevit R.E., Martin A., RA Maruyama H., King M.C., Kawakami H.; RT "Mutations in Twinkle primase-helicase cause Perrault syndrome with RT neurologic features."; RL Neurology 83:2054-2061(2014). CC -!- FUNCTION: [Isoform 1]: Mitochondrial helicase involved in mtDNA CC replication and repair (PubMed:12975372, PubMed:15167897, CC PubMed:17324440, PubMed:18039713, PubMed:18971204, PubMed:25824949, CC PubMed:26887820, PubMed:27226550). Might have a role in mtDNA repair CC (PubMed:27226550). Has DNA strand separation activity needed to form a CC processive replication fork for leading strand synthesis which is CC catalyzed by the formation of a replisome complex with POLG and mtSDB CC (PubMed:12975372, PubMed:15167897, PubMed:18039713, PubMed:22383523, CC PubMed:26887820, PubMed:27226550). Preferentially unwinds DNA CC substrates with pre-existing 5'-and 3'- single-stranded tails but is CC also active on a 5'- flap substrate (PubMed:12975372, PubMed:15167897, CC PubMed:18039713, PubMed:22383523, PubMed:26887820, PubMed:27226550). CC Can dissociate the invading strand of immobile or mobile D-loop DNA CC structures irrespective of the single strand polarity of the third CC strand (PubMed:27226550). In addition to its DNA strand separation CC activity, also has DNA strand annealing, DNA strand-exchange and DNA CC branch migration activities (PubMed:22383523, PubMed:26887820, CC PubMed:27226550). {ECO:0000269|PubMed:12975372, CC ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:17324440, CC ECO:0000269|PubMed:18039713, ECO:0000269|PubMed:18971204, CC ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949, CC ECO:0000269|PubMed:26887820, ECO:0000269|PubMed:27226550}. CC -!- FUNCTION: [Isoform 2]: Lack DNA unwinding and ATP hydrolysis activities CC (PubMed:18039713). Does not bind single-stranded or double-stranded DNA CC (PubMed:18039713). {ECO:0000269|PubMed:18039713}. CC -!- CATALYTIC ACTIVITY: [Isoform 1]: CC Reaction=ATP + H2O = ADP + phosphate + H(+); Xref=Rhea:RHEA:13065, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=5.6.2.3; CC Evidence={ECO:0000269|PubMed:12975372, ECO:0000269|PubMed:17324440, CC ECO:0000269|PubMed:18039713, ECO:0000269|PubMed:18971204, CC ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949, CC ECO:0000269|PubMed:27226550, ECO:0000269|PubMed:35914129}; CC -!- CATALYTIC ACTIVITY: [Isoform 1]: CC Reaction=Couples ATP hydrolysis with the unwinding of duplex DNA at the CC replication fork by translocating in the 5'-3' direction.; CC EC=5.6.2.3; Evidence={ECO:0000269|PubMed:12975372, CC ECO:0000269|PubMed:17324440, ECO:0000269|PubMed:18039713, CC ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:22383523, CC ECO:0000269|PubMed:25824949, ECO:0000269|PubMed:27226550, CC ECO:0000269|PubMed:35914129}; CC -!- ACTIVITY REGULATION: [Isoform 1]: Strand annealing activity is CC inhibited by 150 mM NaCl (in vitro). {ECO:0000269|PubMed:22383523}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: [Isoform 1]: CC Kinetic parameters: CC KM=1.7 mM for UTP (using ssM13mp18 as DNA substrate) CC {ECO:0000269|PubMed:22383523}; CC KM=1.6 mM for UTP (using ssDNA as DNA substrate) CC {ECO:0000269|PubMed:22383523}; CC KM=1.4 mM for UTP (using forked dsDNA as DNA substrate) CC {ECO:0000269|PubMed:22383523}; CC KM=3.4 mM for UTP (using no DNA as substrate) CC {ECO:0000269|PubMed:22383523}; CC -!- SUBUNIT: Interacts with LONP1. {ECO:0000269|PubMed:14739292}. CC -!- SUBUNIT: [Isoform 1]: Homohexamer (via C-terminus), which assembles in CC a ring-like structure (PubMed:17324440, PubMed:18039713, CC PubMed:18971204, PubMed:22383523, PubMed:25824949, PubMed:30496414). CC Homoheptamer, which assembles in a ring-like structure CC (PubMed:25824949, PubMed:30496414, PubMed:35914129). Homooctamer, which CC assembles in a ring-like structure (PubMed:35914129). Oligomers may CC sequentially eject two monomers (octamer>heptamer>hexamer) upon DNA CC binding (PubMed:35914129). Oligomerization is Mg(2+), nucleotide and CC DNA-independent, however, Mg(2+) and nucleotide stabilize the CC homohexameric form (PubMed:18039713). Interacts with POLG in vitro CC (PubMed:15167897). {ECO:0000269|PubMed:15167897, CC ECO:0000269|PubMed:17324440, ECO:0000269|PubMed:18039713, CC ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:22383523, CC ECO:0000269|PubMed:25824949, ECO:0000269|PubMed:30496414, CC ECO:0000269|PubMed:35914129}. CC -!- SUBUNIT: [Isoform 2]: Monomer (PubMed:18039713). Does not form CC oligomers (PubMed:18039713). {ECO:0000269|PubMed:18039713}. CC -!- INTERACTION: CC Q96RR1; Q08380: LGALS3BP; NbExp=2; IntAct=EBI-716458, EBI-354956; CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix, mitochondrion nucleoid CC {ECO:0000269|PubMed:11431692, ECO:0000269|PubMed:18971204}. CC Mitochondrion inner membrane {ECO:0000303|PubMed:34950192}; Peripheral CC membrane protein {ECO:0000269|PubMed:34950192}. Note=Colocalizes with CC mtDNA in mitochondrial nucleoids, a nucleoproteins complex consisting CC of a number of copies of proteins associated with mtDNA, probably CC involved in mtDNA maintenance and expression (PubMed:11431692). CC Associates with phospholipid membranes via electrostatic binding (By CC similarity). Preferentially associates with membranes enriched with CC cardiolipin, a lipid abundant in the mitochondrial inner membrane CC (PubMed:34950192). ATPase and helicase activity is enhanced by binding CC to lipid membranes (PubMed:34950192). {ECO:0000250|UniProtKB:Q9VL76, CC ECO:0000269|PubMed:11431692, ECO:0000269|PubMed:34950192}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q96RR1-1; Sequence=Displayed; CC Name=2; Synonyms=Twinky; CC IsoId=Q96RR1-2; Sequence=VSP_015960, VSP_015961; CC Name=3; CC IsoId=Q96RR1-3; Sequence=VSP_015959; CC -!- TISSUE SPECIFICITY: High relative levels in skeletal muscle, testis and CC pancreas. Lower levels of expression in the heart, brain, placenta, CC lung, liver, kidney, spleen, thymus, prostate, ovary, small intestine, CC colon and leukocytes. Expression is coregulated with MRPL43. CC {ECO:0000269|PubMed:11431692, ECO:0000269|PubMed:15509589}. CC -!- DOMAIN: N-terminus enhances protein stability and hexamer formation, CC which is important for DNA binding, and is required for DNA helicase CC activity and, ultimately, for mtDNA replisome processivity. CC {ECO:0000269|PubMed:18039713}. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 3 (PEOA3) [MIM:609286]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:11431692, CC ECO:0000269|PubMed:12163192, ECO:0000269|PubMed:12921794, CC ECO:0000269|PubMed:15668446, ECO:0000269|PubMed:16639411, CC ECO:0000269|PubMed:17614277, ECO:0000269|PubMed:18396044, CC ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:19353676, CC ECO:0000269|PubMed:19428252, ECO:0000269|PubMed:20479361, CC ECO:0000269|PubMed:20880070}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 7 (MTDPS7) [MIM:271245]: CC A severe disease associated with mitochondrial dysfunction. Some CC patients are affected by progressive atrophy of the cerebellum, brain CC stem, the spinal cord, and sensory axonal neuropathy. Clinical features CC include hypotonia, athetosis, ataxia, ophthalmoplegia, sensorineural CC hearing deficit, sensory axonal neuropathy, epileptic encephalopathy CC and female hypogonadism. In some individuals liver dysfunction and CC multi-organ failure is present. {ECO:0000269|PubMed:16135556, CC ECO:0000269|PubMed:17722119, ECO:0000269|PubMed:17921179, CC ECO:0000269|PubMed:19853444, ECO:0000269|PubMed:22353293}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Perrault syndrome 5 (PRLTS5) [MIM:616138]: A form of Perrault CC syndrome, a sex-influenced disorder characterized by sensorineural CC deafness in both males and females, and ovarian dysgenesis in females. CC Affected females have primary amenorrhea, streak gonads, and CC infertility, whereas affected males show normal pubertal development CC and are fertile. PRLTS5 is an autosomal recessive form characterized by CC progressive ataxia, axonal neuropathy, hyporeflexia and abnormal eye CC movements, in addition to deafness and ovarian dysgenesis. CC {ECO:0000269|PubMed:25355836}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- CAUTION: The N-terminus contains a putative primase-like domain; CC however the absence of the zinc binding domain and other motifs CC important for catalysis suggests that TWNK lacks primase activity. CC {ECO:0000305|PubMed:25824949}. CC -!- CAUTION: In vitro, can catalyze the hydrolysis of different nucleotide CC triphosphate (NTP) substrates with different efficiency. CC {ECO:0000269|PubMed:12975372, ECO:0000269|PubMed:18971204, CC ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF292004; AAK69558.1; -; mRNA. DR EMBL; AF292005; AAK69559.1; -; mRNA. DR EMBL; BX640829; CAE45905.1; -; mRNA. DR EMBL; AL133215; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; EU543650; ACB21043.1; -; Genomic_DNA. DR EMBL; CH471066; EAW49794.1; -; Genomic_DNA. DR EMBL; BC013349; AAH13349.1; -; mRNA. DR CCDS; CCDS53570.1; -. [Q96RR1-2] DR CCDS; CCDS7506.1; -. [Q96RR1-1] DR RefSeq; NP_001157284.1; NM_001163812.2. [Q96RR1-2] DR RefSeq; NP_068602.2; NM_021830.4. [Q96RR1-1] DR PDB; 7T8B; EM; 3.80 A; A/B/C/D/E/F/G/H=1-684. DR PDB; 7T8C; EM; 4.50 A; A/B/C/D/E/F/G=1-684. DR PDBsum; 7T8B; -. DR PDBsum; 7T8C; -. DR AlphaFoldDB; Q96RR1; -. DR EMDB; EMD-25743; -. DR EMDB; EMD-25744; -. DR SMR; Q96RR1; -. DR BioGRID; 121166; 148. DR FunCoup; Q96RR1; 1571. DR IntAct; Q96RR1; 83. DR MINT; Q96RR1; -. DR STRING; 9606.ENSP00000309595; -. DR GlyGen; Q96RR1; 1 site. DR iPTMnet; Q96RR1; -. DR PhosphoSitePlus; Q96RR1; -. DR BioMuta; TWNK; -. DR DMDM; 74752111; -. DR jPOST; Q96RR1; -. DR MassIVE; Q96RR1; -. DR PaxDb; 9606-ENSP00000309595; -. DR PeptideAtlas; Q96RR1; -. DR ProteomicsDB; 78006; -. [Q96RR1-1] DR ProteomicsDB; 78007; -. [Q96RR1-2] DR ProteomicsDB; 78008; -. [Q96RR1-3] DR Pumba; Q96RR1; -. DR Antibodypedia; 1261; 217 antibodies from 25 providers. DR DNASU; 56652; -. DR Ensembl; ENST00000311916.8; ENSP00000309595.2; ENSG00000107815.10. [Q96RR1-1] DR Ensembl; ENST00000370228.2; ENSP00000359248.1; ENSG00000107815.10. [Q96RR1-2] DR Ensembl; ENST00000643860.1; ENSP00000494389.1; ENSG00000107815.10. [Q96RR1-3] DR GeneID; 56652; -. DR KEGG; hsa:56652; -. DR MANE-Select; ENST00000311916.8; ENSP00000309595.2; NM_021830.5; NP_068602.2. DR UCSC; uc001ksf.3; human. [Q96RR1-1] DR AGR; HGNC:1160; -. DR ClinPGx; PA162377675; -. DR CTD; 56652; -. DR DisGeNET; 56652; -. DR GeneCards; TWNK; -. DR HGNC; HGNC:1160; TWNK. DR HPA; ENSG00000107815; Low tissue specificity. DR MalaCards; TWNK; -. DR MIM; 271245; phenotype. DR MIM; 606075; gene. DR MIM; 609286; phenotype. DR MIM; 616138; phenotype. DR OpenTargets; ENSG00000107815; -. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR Orphanet; 1186; Infantile-onset spinocerebellar ataxia. DR Orphanet; 363534; Mitochondrial DNA depletion syndrome, hepatocerebrorenal form. DR Orphanet; 642945; Perrault syndrome type 1. DR Orphanet; 642976; Perrault syndrome type 2. DR Orphanet; 70595; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome. DR VEuPathDB; HostDB:ENSG00000107815; -. DR eggNOG; KOG2373; Eukaryota. DR GeneTree; ENSGT00390000004495; -. DR HOGENOM; CLU_012336_1_0_1; -. DR InParanoid; Q96RR1; -. DR OMA; GIRWSRF; -. DR OrthoDB; 275278at2759; -. DR PAN-GO; Q96RR1; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q96RR1; -. DR BRENDA; 3.6.4.12; 2681. DR PathwayCommons; Q96RR1; -. DR Reactome; R-HSA-2151201; Transcriptional activation of mitochondrial biogenesis. DR Reactome; R-HSA-9837999; Mitochondrial protein degradation. DR Reactome; R-HSA-9913635; Strand-asynchronous mitochondrial DNA replication. DR SignaLink; Q96RR1; -. DR Agora; ENSG00000107815; -. DR BioGRID-ORCS; 56652; 354 hits in 1149 CRISPR screens. DR ChiTaRS; TWNK; human. DR GeneWiki; PEO1; -. DR GenomeRNAi; 56652; -. DR Pharos; Q96RR1; Tbio. DR PRO; PR:Q96RR1; -. DR Proteomes; UP000005640; Chromosome 10. DR RNAct; Q96RR1; protein. DR Bgee; ENSG00000107815; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 139 other cell types or tissues. DR ExpressionAtlas; Q96RR1; baseline and differential. DR GO; GO:0000262; C:mitochondrial chromosome; IDA:FlyBase. DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome. DR GO; GO:0042645; C:mitochondrial nucleoid; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; HTP:FlyBase. DR GO; GO:0043139; F:5'-3' DNA helicase activity; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0016887; F:ATP hydrolysis activity; IDA:FlyBase. DR GO; GO:0003678; F:DNA helicase activity; IBA:GO_Central. DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB. DR GO; GO:0008289; F:lipid binding; IDA:FlyBase. DR GO; GO:0002020; F:protease binding; IPI:UniProtKB. DR GO; GO:0003697; F:single-stranded DNA binding; IDA:UniProtKB. DR GO; GO:0006261; P:DNA-templated DNA replication; IDA:FlyBase. DR GO; GO:0006264; P:mitochondrial DNA replication; IMP:UniProtKB. DR GO; GO:0006390; P:mitochondrial transcription; IMP:UniProtKB. DR GO; GO:0034214; P:protein hexamerization; IDA:UniProtKB. DR CDD; cd01029; TOPRIM_primases; 1. DR CDD; cd01122; Twinkle_C; 1. DR FunFam; 3.40.1360.10:FF:000008; Mitochondrial helicase twinkle; 1. DR FunFam; 3.40.50.300:FF:000845; Mitochondrial helicase twinkle; 1. DR Gene3D; 3.40.1360.10; -; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR InterPro; IPR007694; DNA_helicase_DnaB-like_C. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR034154; TOPRIM_DnaG/twinkle. DR InterPro; IPR027032; Twinkle-like. DR PANTHER; PTHR12873; T7-LIKE MITOCHONDRIAL DNA HELICASE; 1. DR PANTHER; PTHR12873:SF0; TWINKLE MTDNA HELICASE; 1. DR Pfam; PF13481; AAA_25; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR PROSITE; PS51199; SF4_HELICASE; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Deafness; Disease variant; KW DNA replication; Helicase; Hydrolase; Isomerase; Lipid-binding; Membrane; KW Mitochondrion; Mitochondrion inner membrane; Mitochondrion nucleoid; KW Neurodegeneration; Neuropathy; Nucleotide-binding; KW Primary mitochondrial disease; Progressive external ophthalmoplegia; KW Proteomics identification; Reference proteome; Transit peptide. FT TRANSIT 1..31 FT /note="Mitochondrion" FT /evidence="ECO:0000255" FT CHAIN 32..684 FT /note="Twinkle mtDNA helicase" FT /id="PRO_0000042640" FT DOMAIN 384..635 FT /note="SF4 helicase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00596" FT REGION 1..121 FT /note="Contributes to single strand DNA binding activity" FT /evidence="ECO:0000269|PubMed:18039713" FT REGION 54..214 FT /note="N-terminal region (NTR)" FT /evidence="ECO:0000269|PubMed:35914129" FT REGION 121..372 FT /note="Required for hexamers formation and DNA helicase FT activity" FT /evidence="ECO:0000269|PubMed:18039713" FT REGION 215..335 FT /note="Primase-like domain" FT /evidence="ECO:0000269|PubMed:35914129" FT REGION 405..590 FT /note="Maybe required for stable oligomeric structure" FT /evidence="ECO:0000269|PubMed:17324440" FT REGION 637..684 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 640..684 FT /note="Might negatively regulate ATPase activity" FT /evidence="ECO:0000269|PubMed:17324440" FT COMPBIAS 659..677 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 415..422 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00596" FT VAR_SEQ 532..684 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_015959" FT VAR_SEQ 579..582 FT /note="ASQE -> VSGL (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11431692, FT ECO:0000303|PubMed:15489334" FT /id="VSP_015960" FT VAR_SEQ 583..684 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11431692, FT ECO:0000303|PubMed:15489334" FT /id="VSP_015961" FT VARIANT 303 FT /note="R -> Q (in PEOA3; dbSNP:rs137852956)" FT /evidence="ECO:0000269|PubMed:19353676, FT ECO:0000269|PubMed:20479361" FT /id="VAR_065102" FT VARIANT 303 FT /note="R -> W (in PEOA3; also detected in a case showing FT digenic inheritance; dbSNP:rs1159929268)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:19428252, FT ECO:0000269|PubMed:20479361" FT /id="VAR_023647" FT VARIANT 315 FT /note="W -> L (in PEOA3; reduced single-strand DNA binding; FT increased heptamer oligomerization; increased stability of FT the closed or 'compacted' conformation; dbSNP:rs111033575)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:30496414, ECO:0000269|PubMed:35914129" FT /id="VAR_023648" FT VARIANT 315 FT /note="W -> S (in PEOA3; reduces helicase activity; reduced FT single-strand DNA binding)" FT /evidence="ECO:0000269|PubMed:18575922, FT ECO:0000269|PubMed:18971204" FT /id="VAR_065103" FT VARIANT 318 FT /note="A -> T (in MTDPS7; dbSNP:rs80356542)" FT /evidence="ECO:0000269|PubMed:17921179" FT /id="VAR_065104" FT VARIANT 319 FT /note="K -> E (in PEOA3; the phenotype highly overlaps with FT sensory ataxic neuropathy dysarthria and ophthalmoparesis; FT reduces helicase activity and single-strand DNA binding; FT dbSNP:rs80356543)" FT /evidence="ECO:0000269|PubMed:15668446, FT ECO:0000269|PubMed:18971204" FT /id="VAR_023649" FT VARIANT 319 FT /note="K -> T (in PEOA3)" FT /evidence="ECO:0000269|PubMed:12921794" FT /id="VAR_023650" FT VARIANT 334 FT /note="R -> P (in PEOA3)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065105" FT VARIANT 334 FT /note="R -> Q (in PEO; sporadic case; the patient also FT carries the S-848 mutation in the POLG gene suggesting FT digenic inheritance; retains hexamer and heptamer FT formation; dbSNP:rs28937887)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:12872260, ECO:0000269|PubMed:20479361, FT ECO:0000269|PubMed:30496414" FT /id="VAR_023651" FT VARIANT 335 FT /note="P -> L (in PEOA3; displays unusual oligomeric FT forms)" FT /evidence="ECO:0000269|PubMed:12163192, FT ECO:0000269|PubMed:30496414" FT /id="VAR_023652" FT VARIANT 348 FT /note="G -> R (in dbSNP:rs62626271)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_062268" FT VARIANT 354 FT /note="R -> P (in PEOA3; dbSNP:rs111033576)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:20479361" FT /id="VAR_023653" FT VARIANT 357 FT /note="R -> P (in PEOA3; dbSNP:rs758026634)" FT /evidence="ECO:0000269|PubMed:17614277, FT ECO:0000269|PubMed:20479361" FT /id="VAR_065106" FT VARIANT 359 FT /note="A -> T (in PEOA3; reduces helicase activity; FT dbSNP:rs111033573)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:20479361" FT /id="VAR_023654" FT VARIANT 360 FT /note="L -> G (in MTDPS7; patients manifest multi-organ FT failure; requires 2 nucleotide substitutions)" FT /evidence="ECO:0000269|PubMed:19853444" FT /id="VAR_065107" FT VARIANT 362 FT /note="A -> P (in PEOA3; dbSNP:rs1554887075)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065108" FT VARIANT 363 FT /note="W -> L (in PEOA3)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065109" FT VARIANT 367 FT /note="I -> T (in PEOA3)" FT /evidence="ECO:0000269|PubMed:11431692" FT /id="VAR_023655" FT VARIANT 368 FT /note="V -> I (in dbSNP:rs17113613)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:12557300, ECO:0000269|PubMed:16639411, FT ECO:0000269|Ref.4" FT /id="VAR_023656" FT VARIANT 369 FT /note="S -> P (in PEOA3; reduces helicase activity; FT increases single strand DNA affinity; reduces closed-ring FT quaternary structure formation)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:30496414" FT /id="VAR_023657" FT VARIANT 369 FT /note="S -> Y (in PEOA3; dbSNP:rs111033579)" FT /evidence="ECO:0000269|PubMed:12163192" FT /id="VAR_023658" FT VARIANT 370 FT /note="F -> C (in PEOA3)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065110" FT VARIANT 370 FT /note="F -> L (in PEOA3; dbSNP:rs863223920)" FT /evidence="ECO:0000269|PubMed:18396044" FT /id="VAR_065111" FT VARIANT 374 FT /note="R -> Q (in PEOA3; reduces helicase activity and FT alters nucleoid structure; dbSNP:rs1554887097)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18971204, FT ECO:0000269|PubMed:20479361, ECO:0000269|PubMed:20880070" FT /id="VAR_023659" FT VARIANT 381 FT /note="L -> P (in PEOA3; reduces closed-ring quaternary FT structure formation; dbSNP:rs111033577)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:20479361, ECO:0000269|PubMed:30496414" FT /id="VAR_023660" FT VARIANT 391 FT /note="R -> H (in PRLTS5; dbSNP:rs556445621)" FT /evidence="ECO:0000269|PubMed:25355836" FT /id="VAR_072657" FT VARIANT 426 FT /note="S -> N (in PEOA3)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065112" FT VARIANT 427 FT /note="E -> G (in dbSNP:rs11542126)" FT /id="VAR_051267" FT VARIANT 441 FT /note="W -> G (in PRLTS5; dbSNP:rs672601361)" FT /evidence="ECO:0000269|PubMed:25355836" FT /id="VAR_072658" FT VARIANT 456 FT /note="L -> V (in MTDPS7; infantile spinocerebellar ataxia FT phenotype; dbSNP:rs386834145)" FT /evidence="ECO:0000269|PubMed:22353293" FT /id="VAR_067722" FT VARIANT 457 FT /note="T -> I (in MTDPS7; affects helicase activity; FT dbSNP:rs80356544)" FT /evidence="ECO:0000269|PubMed:17722119" FT /id="VAR_039045" FT VARIANT 458 FT /note="Q -> H (in PEOA3; dbSNP:rs1554887213)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065113" FT VARIANT 460 FT /note="A -> P (in PEOA3)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065114" FT VARIANT 474 FT /note="W -> C (in PEOA3; reduces helicase activity and FT alters nucleoid structure; dbSNP:rs111033574)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:18971204" FT /id="VAR_023661" FT VARIANT 474 FT /note="W -> S (in PEOA3; dbSNP:rs11542127)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065115" FT VARIANT 475 FT /note="A -> D (in PEOA3)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065116" FT VARIANT 475 FT /note="A -> P (in PEOA3; dbSNP:rs111033572)" FT /evidence="ECO:0000269|PubMed:11431692" FT /id="VAR_023662" FT VARIANT 478 FT /note="F -> I (in PEOA3)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065117" FT VARIANT 479 FT /note="E -> K (in PEOA3; dbSNP:rs1085307937)" FT /evidence="ECO:0000269|PubMed:18575922, FT ECO:0000269|PubMed:20479361" FT /id="VAR_065118" FT VARIANT 507 FT /note="V -> I (in PRLTS5; dbSNP:rs369588002)" FT /evidence="ECO:0000269|PubMed:25355836" FT /id="VAR_072659" FT VARIANT 508 FT /note="Y -> C (in MTDPS7; dbSNP:rs80356540)" FT /evidence="ECO:0000269|PubMed:16135556, FT ECO:0000269|PubMed:17921179" FT /id="VAR_043797" FT VARIANT 585 FT /note="N -> S (in PRLTS5; dbSNP:rs672601360)" FT /evidence="ECO:0000269|PubMed:25355836" FT /id="VAR_072660" FT VARIANT 634 FT /note="N -> K (in dbSNP:rs62626293)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_062269" FT MUTAGEN 421 FT /note="K->A: Loss of helicase activity on 5'-tailed FT substrate." FT /evidence="ECO:0000269|PubMed:22383523" FT CONFLICT 351 FT /note="N -> D (in Ref. 3; CAE45905)" FT /evidence="ECO:0000305" SQ SEQUENCE 684 AA; 77154 MW; 58186043888234DA CRC64; MWVLLRSGYP LRILLPLRGE WMGRRGLPRN LAPGPPRRRY RKETLQALDM PVLPVTATEI RQYLRGHGIP FQDGHSCLRA LSPFAESSQL KGQTGVTTSF SLFIDKTTGH FLCMTSLAEG SWEDFQASVE GRGDGAREGF LLSKAPEFED SEEVRRIWNR AIPLWELPDQ EEVQLADTMF GLTKVTDDTL KRFSVRYLRP ARSLVFPWFS PGGSGLRGLK LLEAKCQGDG VSYEETTIPR PSAYHNLFGL PLISRRDAEV VLTSRELDSL ALNQSTGLPT LTLPRGTTCL PPALLPYLEQ FRRIVFWLGD DLRSWEAAKL FARKLNPKRC FLVRPGDQQP RPLEALNGGF NLSRILRTAL PAWHKSIVSF RQLREEVLGE LSNVEQAAGL RWSRFPDLNR ILKGHRKGEL TVFTGPTGSG KTTFISEYAL DLCSQGVNTL WGSFEISNVR LARVMLTQFA EGRLEDQLDK YDHWADRFED LPLYFMTFHG QQSIRTVIDT MQHAVYVYDI CHVIIDNLQF MMGHEQLSTD RIAAQDYIIG VFRKFATDNN CHVTLVIHPR KEDDDKELQT ASIFGSAKAS QEADNVLILQ DRKLVTGPGK RYLQVSKNRF DGDVGVFPLE FNKNSLTFSI PPKNKARLKK IKDDTGPVAK KPSSGKKGAT TQNSEICSGQ APTPDQPDTS KRSK // ID REST_HUMAN Reviewed; 1097 AA. AC Q13127; A2RUE0; B9EGJ0; Q12956; Q12957; Q13134; Q59ER1; Q8IWI3; DT 12-DEC-2006, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 3. DT 28-JAN-2026, entry version 209. DE RecName: Full=RE1-silencing transcription factor; DE AltName: Full=Neural-restrictive silencer factor; DE AltName: Full=X2 box repressor; GN Name=REST; Synonyms=NRSF, XBR; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION. RX PubMed=7697725; DOI=10.1016/0092-8674(95)90298-8; RA Chong J.A., Tapia-Ramirez J., Kim S., Toledo-Aral J.J., Zheng Y., RA Boutros M.C., Altshuller Y.M., Frohman M.A., Kraner S.D., Mandel G.; RT "REST: a mammalian silencer protein that restricts sodium channel gene RT expression to neurons."; RL Cell 80:949-957(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), NUCLEOTIDE SEQUENCE [MRNA] OF 1-599 RP (ISOFORM 1), AND FUNCTION. RX PubMed=7871435; DOI=10.1126/science.7871435; RA Schoenherr C.J., Anderson D.J.; RT "The neuron-restrictive silencer factor (NRSF): a coordinate repressor of RT multiple neuron-specific genes."; RL Science 267:1360-1363(1995). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, AND RP VARIANT LEU-797. RX PubMed=8568247; RA Scholl T., Stevens M.B., Mahanta S., Strominger J.L.; RT "A zinc finger protein that represses transcription of the human MHC class RT II gene, DPA."; RL J. Immunol. 156:1448-1457(1996). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., RA Ohara O., Nagase T., Kikuno R.F.; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ILE-626. RC TISSUE=Testis, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP ALTERNATIVE SPLICING (ISOFORMS 3 AND 4). RX PubMed=10521596; DOI=10.1016/s0169-328x(99)00196-5; RA Palm K., Metsis M., Timmusk T.; RT "Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR RT is frequent in neuroblastomas and conserved in human, mouse and rat."; RL Brain Res. Mol. Brain Res. 72:30-39(1999). RN [9] RP FUNCTION, AND INTERACTION WITH RCOR1. RX PubMed=10449787; DOI=10.1073/pnas.96.17.9873; RA Andres M.E., Burger C., Peral-Rubio M.J., Battaglioli E., Anderson M.E., RA Grimes J., Dallman J., Ballas N., Mandel G.; RT "CoREST: a functional corepressor required for regulation of neural- RT specific gene expression."; RL Proc. Natl. Acad. Sci. U.S.A. 96:9873-9878(1999). RN [10] RP FUNCTION, AND INTERACTION WITH RCOR1 AND SIN3A. RX PubMed=10734093; DOI=10.1074/jbc.275.13.9461; RA Grimes J.A., Nielsen S.J., Battaglioli E., Miska E.A., Speh J.C., RA Berry D.L., Atouf F., Holdener B.C., Mandel G., Kouzarides T.; RT "The co-repressor mSin3A is a functional component of the REST-CoREST RT repressor complex."; RL J. Biol. Chem. 275:9461-9467(2000). RN [11] RP FUNCTION. RX PubMed=11779185; DOI=10.1006/bbrc.2001.6194; RA Tabuchi A., Yamada T., Sasagawa S., Naruse Y., Mori N., Tsuda M.; RT "REST4-mediated modulation of REST/NRSF-silencing function during BDNF gene RT promoter activation."; RL Biochem. Biophys. Res. Commun. 290:415-420(2002). RN [12] RP FUNCTION, AND SUBCELLULAR LOCATION (ISOFORM 3). RX PubMed=11741002; DOI=10.1016/s0197-0186(01)00091-2; RA Magin A., Lietz M., Cibelli G., Thiel G.; RT "RE-1 silencing transcription factor-4 (REST4) is neither a transcriptional RT repressor nor a de-repressor."; RL Neurochem. Int. 40:195-202(2002). RN [13] RP FUNCTION. RX PubMed=12399542; DOI=10.1126/science.1076469; RA Lunyak V.V., Burgess R., Prefontaine G.G., Nelson C., Sze S.-H., RA Chenoweth J., Schwartz P., Pevzner P.A., Glass C., Mandel G., RA Rosenfeld M.G.; RT "Corepressor-dependent silencing of chromosomal regions encoding neuronal RT genes."; RL Science 298:1747-1752(2002). RN [14] RP ERRATUM OF PUBMED:12399542. RA Lunyak V.V., Burgess R., Prefontaine G.G., Nelson C., Sze S.-H., RA Chenoweth J., Schwartz P., Pevzner P.A., Glass C., Mandel G., RA Rosenfeld M.G.; RL Science 299:1663-1663(2003). RN [15] RP INTERACTION WITH PRICKLE1. RC TISSUE=Brain; RX PubMed=14645515; DOI=10.1128/mcb.23.24.9025-9031.2003; RA Shimojo M., Hersh L.B.; RT "REST/NRSF-interacting LIM domain protein, a putative nuclear translocation RT receptor."; RL Mol. Cell. Biol. 23:9025-9031(2003). RN [16] RP INTERACTION WITH PRICKLE1, SUBCELLULAR LOCATION (ISOFORMS 1; 2; 3 AND 4), RP AND MUTAGENESIS OF 512-LYS--LYS-522. RX PubMed=16442230; DOI=10.1016/j.neulet.2005.12.080; RA Shimojo M.; RT "Characterization of the nuclear targeting signal of REST/NRSF."; RL Neurosci. Lett. 398:161-166(2006). RN [17] RP FUNCTION, INTERACTION WITH CDYL; EHMT1 AND EHMT2, AND IDENTIFICATION IN A RP COMPLEX WITH CDYL; SETB1; EHMT1; EHMT2 AND WIZ. RX PubMed=19061646; DOI=10.1016/j.molcel.2008.10.025; RA Mulligan P., Westbrook T.F., Ottinger M., Pavlova N., Chang B., Macia E., RA Shi Y.J., Barretina J., Liu J., Howley P.M., Elledge S.J., Shi Y.; RT "CDYL bridges REST and histone methyltransferases for gene repression and RT suppression of cellular transformation."; RL Mol. Cell 32:718-726(2008). RN [18] RP INTERACTION WITH FBXW11 AND BTRC, DEVELOPMENTAL STAGE, PHOSPHORYLATION, RP UBIQUITINATION BY BTRC, AND MUTAGENESIS OF 1009-GLU--SER-1013. RX PubMed=18354482; DOI=10.1038/nature06641; RA Guardavaccaro D., Frescas D., Dorrello N.V., Peschiaroli A., Multani A.S., RA Cardozo T., Lasorella A., Iavarone A., Chang S., Hernando E., Pagano M.; RT "Control of chromosome stability by the beta-TrCP-REST-Mad2 axis."; RL Nature 452:365-369(2008). RN [19] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-864, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [21] RP INTERACTION WITH ZFP90. RX PubMed=21284946; DOI=10.1016/j.yjmcc.2011.01.017; RA Hata L., Murakami M., Kuwahara K., Nakagawa Y., Kinoshita H., Usami S., RA Yasuno S., Fujiwara M., Kuwabara Y., Minami T., Yamada Y., Yamada C., RA Nakao K., Ueshima K., Nishikimi T., Nakao K.; RT "Zinc-finger protein 90 negatively regulates neuron-restrictive silencer RT factor-mediated transcriptional repression of fetal cardiac genes."; RL J. Mol. Cell. Cardiol. 50:972-981(2011). RN [22] RP FUNCTION, INTERACTION WITH USP7, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP INDUCTION, UBIQUITINATION BY BTRC, DEUBIQUITINATION BY USP7, AND RP MUTAGENESIS OF SER-313 AND SER-1042. RX PubMed=21258371; DOI=10.1038/ncb2153; RA Huang Z., Wu Q., Guryanova O.A., Cheng L., Shou W., Rich J.N., Bao S.; RT "Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural RT progenitor cells."; RL Nat. Cell Biol. 13:142-152(2011). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-864, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [24] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, RP AND INDUCTION BY WNT SIGNALING; AGING AND OXIDATIVE STRESS. RX PubMed=24670762; DOI=10.1038/nature13163; RA Lu T., Aron L., Zullo J., Pan Y., Kim H., Chen Y., Yang T.H., Kim H.M., RA Drake D., Liu X.S., Bennett D.A., Colaiacovo M.P., Yankner B.A.; RT "REST and stress resistance in ageing and Alzheimer's disease."; RL Nature 507:448-454(2014). RN [25] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=26053433; DOI=10.1038/srep11207; RA Lee N.S., Evgrafov O.V., Souaiaia T., Bonyad A., Herstein J., Lee J.Y., RA Kim J., Ning Y., Sixto M., Weitz A.C., Lenz H.J., Wang K., Knowles J.A., RA Press M.F., Salvaterra P.M., Shung K.K., Chow R.H.; RT "Non-coding RNAs derived from an alternatively spliced REST transcript RT (REST-003) regulate breast cancer invasiveness."; RL Sci. Rep. 5:11207-11207(2015). RN [26] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=27531581; DOI=10.1038/srep31355; RA Cavadas M.A., Mesnieres M., Crifo B., Manresa M.C., Selfridge A.C., RA Keogh C.E., Fabian Z., Scholz C.C., Nolan K.A., Rocha L.M., Tambuwala M.M., RA Brown S., Wdowicz A., Corbett D., Murphy K.J., Godson C., Cummins E.P., RA Taylor C.T., Cheong A.; RT "REST is a hypoxia-responsive transcriptional repressor."; RL Sci. Rep. 6:31355-31355(2016). RN [27] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=30684677; DOI=10.1016/j.neulet.2019.01.042; RA Kawamura M., Sato S., Matsumoto G., Fukuda T., Shiba-Fukushima K., Noda S., RA Takanashi M., Mori N., Hattori N.; RT "Loss of nuclear REST/NRSF in aged-dopaminergic neurons in Parkinson's RT disease patients."; RL Neurosci. Lett. 699:59-63(2019). RN [28] RP STRUCTURE BY NMR OF 43-57 IN COMPLEX WITH SIN3B, AND INTERACTION WITH RP SIN3B. RX PubMed=16288918; DOI=10.1016/j.jmb.2005.10.008; RA Nomura M., Uda-Tochio H., Murai K., Mori N., Nishimura Y.; RT "The neural repressor NRSF/REST binds the PAH1 domain of the Sin3 RT corepressor by using its distinct short hydrophobic helix."; RL J. Mol. Biol. 354:903-915(2005). RN [29] RP INVOLVEMENT IN WT6, VARIANTS WT6 PRO-160; TYR-290; ARG-322 AND GLN-412, RP CHARACTERIZATION OF VARIANT PRO-160; TYR-290 AND ARG-322, FUNCTION, AND RP MUTAGENESIS OF GLU-91; MET-420; SER-593; ALA-642 AND HIS-918. RX PubMed=26551668; DOI=10.1038/ng.3440; RA Mahamdallie S.S., Hanks S., Karlin K.L., Zachariou A., Perdeaux E.R., RA Ruark E., Shaw C.A., Renwick A., Ramsay E., Yost S., Elliott A., Birch J., RA Capra M., Gray J., Hale J., Kingston J., Levitt G., McLean T., Sheridan E., RA Renwick A., Seal S., Stiller C., Sebire N., Westbrook T.F., Rahman N.; RT "Mutations in the transcriptional repressor REST predispose to Wilms RT tumor."; RL Nat. Genet. 47:1471-1474(2015). RN [30] RP INVOLVEMENT IN GINGF5, AND VARIANT GINGF5 437-LEU--GLU-1097 DEL. RX PubMed=28686854; DOI=10.1016/j.ajhg.2017.06.006; RG Baylor-Hopkins Center for Mendelian Genomics; RA Bayram Y., White J.J., Elcioglu N., Cho M.T., Zadeh N., Gedikbasi A., RA Palanduz S., Ozturk S., Cefle K., Kasapcopur O., Coban Akdemir Z., RA Pehlivan D., Begtrup A., Carvalho C.M.B., Paine I.S., Mentes A., RA Bektas-Kayhan K., Karaca E., Jhangiani S.N., Muzny D.M., Gibbs R.A., RA Lupski J.R.; RT "REST final-exon-truncating mutations cause hereditary gingival RT fibromatosis."; RL Am. J. Hum. Genet. 101:149-156(2017). RN [31] RP INVOLVEMENT IN DFNA27, AND ALTERNATIVE SPLICING (ISOFORM 3). RX PubMed=29961578; DOI=10.1016/j.cell.2018.06.004; RA Nakano Y., Kelly M.C., Rehman A.U., Boger E.T., Morell R.J., Kelley M.W., RA Friedman T.B., Banfi B.; RT "Defects in the Alternative Splicing-Dependent Regulation of REST Cause RT Deafness."; RL Cell 174:536-548.E21(2018). CC -!- FUNCTION: Transcriptional repressor which binds neuron-restrictive CC silencer element (NRSE) and represses neuronal gene transcription in CC non-neuronal cells (PubMed:11741002, PubMed:11779185, PubMed:12399542, CC PubMed:26551668, PubMed:7697725, PubMed:7871435, PubMed:8568247). CC Restricts the expression of neuronal genes by associating with two CC distinct corepressors, SIN3A and RCOR1, which in turn recruit histone CC deacetylase to the promoters of REST-regulated genes (PubMed:10449787, CC PubMed:10734093). Mediates repression by recruiting the BHC complex at CC RE1/NRSE sites which acts by deacetylating and demethylating specific CC sites on histones, thereby acting as a chromatin modifier (By CC similarity). Transcriptional repression by REST-CDYL via the CC recruitment of histone methyltransferase EHMT2 may be important in CC transformation suppression (PubMed:19061646). Represses the expression CC of SRRM4 in non-neural cells to prevent the activation of neural- CC specific splicing events and to prevent production of REST isoform 3 CC (By similarity). Repressor activity may be inhibited by forming CC heterodimers with isoform 3, thereby preventing binding to NRSE or CC binding to corepressors and leading to derepression of target genes CC (PubMed:11779185). Also maintains repression of neuronal genes in CC neural stem cells, and allows transcription and differentiation into CC neurons by dissociation from RE1/NRSE sites of target genes (By CC similarity). Thereby is involved in maintaining the quiescent state of CC adult neural stem cells and preventing premature differentiation into CC mature neurons (PubMed:21258371). Plays a role in the developmental CC switch in synaptic NMDA receptor composition during postnatal CC development, by repressing GRIN2B expression and thereby altering NMDA CC receptor properties from containing primarily GRIN2B to primarily CC GRIN2A subunits (By similarity). Acts as a regulator of osteoblast CC differentiation (By similarity). Key repressor of gene expression in CC hypoxia; represses genes in hypoxia by direct binding to an RE1/NRSE CC site on their promoter regions (PubMed:27531581). May also function in CC stress resistance in the brain during aging; possibly by regulating CC expression of genes involved in cell death and in the stress response CC (PubMed:24670762). Repressor of gene expression in the hippocampus CC after ischemia by directly binding to RE1/NRSE sites and recruiting CC SIN3A and RCOR1 to promoters of target genes, thereby promoting changes CC in chromatin modifications and ischemia-induced cell death (By CC similarity). After ischemia, might play a role in repression of miR-132 CC expression in hippocampal neurons, thereby leading to neuronal cell CC death (By similarity). Negatively regulates the expression of SRRM3 in CC breast cancer cell lines (PubMed:26053433). CC {ECO:0000250|UniProtKB:O54963, ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:10449787, ECO:0000269|PubMed:10734093, CC ECO:0000269|PubMed:11741002, ECO:0000269|PubMed:11779185, CC ECO:0000269|PubMed:12399542, ECO:0000269|PubMed:19061646, CC ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:24670762, CC ECO:0000269|PubMed:26053433, ECO:0000269|PubMed:26551668, CC ECO:0000269|PubMed:27531581, ECO:0000269|PubMed:7697725, CC ECO:0000269|PubMed:7871435, ECO:0000269|PubMed:8568247}. CC -!- FUNCTION: [Isoform 3]: Binds to the 3' region of the neuron-restrictive CC silencer element (NRSE), with lower affinity than full-length REST CC isoform 1 (By similarity). Exhibits weaker repressor activity compared CC to isoform 1 (PubMed:11779185). May negatively regulate the repressor CC activity of isoform 1 by binding to isoform 1, thereby preventing its CC binding to NRSE and leading to derepression of target genes CC (PubMed:11779185). However, in another study, does not appear to be CC implicated in repressor activity of a NRSE motif-containing reporter CC construct nor in inhibitory activity on the isoform 1 transcriptional CC repressor activity (PubMed:11741002). Post-transcriptional inactivation CC of REST by SRRM4-dependent alternative splicing into isoform 3 is CC required in mechanosensory hair cells in the inner ear for derepression CC of neuronal genes and hearing (By similarity). CC {ECO:0000250|UniProtKB:Q8VIG1, ECO:0000269|PubMed:11741002, CC ECO:0000269|PubMed:11779185}. CC -!- SUBUNIT: Isoform 1 and isoform 3 form heterodimers (By similarity). CC Isoform 3: Forms homodimers and homooligomers; binds to the neuron- CC restrictive silencer element (NRSE) as monomer (By similarity). CC Interacts with SIN3A, SIN3B and RCOR1 (PubMed:10449787, CC PubMed:10734093, PubMed:16288918). Interacts with CDYL CC (PubMed:19061646). Interacts with EHMT1 and EHMT2 only in the presence CC of CDYL (PubMed:19061646). Part of a complex containing at least CDYL, CC REST, WIZ, SETB1, EHMT1 and EHMT2 (PubMed:19061646). Interacts (via CC zinc-finger DNA-binding domain) with ZFP90 (via N- and C-termini); the CC interaction inhibits REST repressor activity (PubMed:21284946). CC Interacts (via C2H2-type zinc finger 5) with PRICKLE1 (PubMed:14645515, CC PubMed:16442230). Interacts with FBXW11 and BTRC (PubMed:18354482). CC Interacts with USP7 (PubMed:21258371). {ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:10449787, ECO:0000269|PubMed:10734093, CC ECO:0000269|PubMed:14645515, ECO:0000269|PubMed:16288918, CC ECO:0000269|PubMed:16442230, ECO:0000269|PubMed:18354482, CC ECO:0000269|PubMed:19061646, ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:21284946}. CC -!- INTERACTION: CC Q13127; Q9Y297: BTRC; NbExp=10; IntAct=EBI-926706, EBI-307461; CC Q13127; Q9UKB1: FBXW11; NbExp=3; IntAct=EBI-926706, EBI-355189; CC Q13127; P07900: HSP90AA1; NbExp=4; IntAct=EBI-926706, EBI-296047; CC Q13127; P41229: KDM5C; NbExp=3; IntAct=EBI-926706, EBI-1246541; CC Q13127; P51532: SMARCA4; NbExp=2; IntAct=EBI-926706, EBI-302489; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16442230, CC ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:24670762, CC ECO:0000269|PubMed:27531581, ECO:0000269|PubMed:30684677}. Cytoplasm CC {ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:27531581, CC ECO:0000269|PubMed:30684677}. Note=Colocalizes with ZFP90 in the CC nucleus (By similarity). In response to hypoxia, there is a more CC pronounced increase in levels in the nucleus as compared to the CC cytoplasm (PubMed:27531581). In aging neurons, increased levels in the CC nucleus as compared to the cytoplasm (PubMed:24670762, CC PubMed:30684677). {ECO:0000250|UniProtKB:Q8VIG1, CC ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:27531581, CC ECO:0000269|PubMed:30684677}. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm CC {ECO:0000269|PubMed:16442230}. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Nucleus CC {ECO:0000269|PubMed:11741002, ECO:0000269|PubMed:16442230}. CC -!- SUBCELLULAR LOCATION: [Isoform 4]: Cytoplasm CC {ECO:0000269|PubMed:16442230}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Comment=Additional isoforms seem to exist.; CC Name=1; Synonyms=REST1 {ECO:0000303|PubMed:16442230}; CC IsoId=Q13127-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13127-2; Sequence=VSP_022064, VSP_022065; CC Name=3; Synonyms=N4, REST4 {ECO:0000303|PubMed:11779185}; CC IsoId=Q13127-3; Sequence=VSP_022066, VSP_022068; CC Name=4; CC IsoId=Q13127-4; Sequence=VSP_022067; CC -!- TISSUE SPECIFICITY: Expressed in neurons of the prefrontal cortex, in CC hippocampal pyramidal neurons, dentate gyrus granule neurons and CC cerebellar Purkinje and granule neurons (at protein level) CC (PubMed:24670762). Expressed in dopaminergic neurons of the substantia CC nigra (at protein level) (PubMed:30684677). Expressed in neural CC progenitor cells (at protein level) (PubMed:21258371). In patients CC suffering from Alzheimer disease, frontotemporal dementia or dementia CC with Lewy bodies, decreased nuclear levels have been observed in CC neurons of the prefrontal cortex and the hippocampus, but not in CC neurons of the dentate gyrus and cerebellum (at protein level) CC (PubMed:24670762). In patients with Parkinson disease or dementia with CC Lewy bodies, decreased nuclear levels have been observed in CC dopaminergic neurons and in cortical neurons and localization to Lewy CC bodies and pale bodies was detected (at protein level) CC (PubMed:30684677). Expressed at higher levels in weakly invasive breast CC cancer cell lines and at lower levels in highly invasive breast cancer CC lines (at protein level) (PubMed:26053433). Ubiquitous CC (PubMed:8568247). Expressed at higher levels in the tissues of the CC lymphocytic compartment, including spleen, thymus, peripheral blood CC lymphocytes and ovary (PubMed:8568247). {ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:24670762, ECO:0000269|PubMed:26053433, CC ECO:0000269|PubMed:30684677, ECO:0000269|PubMed:8568247}. CC -!- DEVELOPMENTAL STAGE: Expression is cell cycle-dependent with decreased CC levels in G2 phase; mediated by proteasomal degradation (at protein CC level) (PubMed:18354482). In aged individuals, increased expression in CC hippocampal CA1, CA3 and CA4 pyramidal neurons and in dentate granule CC cell neurons, but not in the cerebellum (PubMed:24670762). CC {ECO:0000269|PubMed:18354482, ECO:0000269|PubMed:24670762}. CC -!- INDUCTION: Up-regulated by Wnt signaling (PubMed:24670762). Up- CC regulated in the brain of aging individuals but not in Alzheimer CC disease patients (PubMed:24670762). Up-regulated by oxidative stress CC (PubMed:24670762). Down-regulated during neural progenitor cell CC differentiation (PubMed:21258371). {ECO:0000269|PubMed:21258371, CC ECO:0000269|PubMed:24670762}. CC -!- DOMAIN: The C2H2-type zinc finger 5 is required for nuclear CC localization. {ECO:0000269|PubMed:16442230}. CC -!- PTM: O-glycosylated. {ECO:0000250|UniProtKB:Q8VIG1}. CC -!- PTM: Phosphorylated; phosphorylation is required for ubiquitination. CC {ECO:0000269|PubMed:18354482}. CC -!- PTM: Ubiquitinated; ubiquitination is mediated by BTRC and leads to CC proteasomal degradation in G2 phase (PubMed:18354482, PubMed:21258371). CC Ubiquitination increases during neuronal differentiation CC (PubMed:21258371). Deubiquitinated by USP7; leading to its CC stabilization and promoting the maintenance of neural progenitor cells CC (PubMed:21258371). {ECO:0000269|PubMed:18354482, CC ECO:0000269|PubMed:21258371}. CC -!- DISEASE: Wilms tumor 6 (WT6) [MIM:616806]: A pediatric malignancy of CC kidney, and the most common childhood abdominal malignancy. It is CC caused by the uncontrolled multiplication of renal stem, stromal, and CC epithelial cells. {ECO:0000269|PubMed:26551668}. Note=Disease CC susceptibility is associated with variants affecting the gene CC represented in this entry. CC -!- DISEASE: Fibromatosis, gingival, 5 (GINGF5) [MIM:617626]: An autosomal CC dominant form of hereditary gingival fibromatosis, a rare condition CC characterized by a slow, progressive overgrowth of the gingiva. The CC excess gingival tissue can cover part of or the entire crown, and can CC result in diastemas, teeth displacement, or retention of primary or CC impacted teeth. {ECO:0000269|PubMed:28686854}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Note=An intronic variant that affects alternative splicing of CC REST into isoform 3 and inactivation of REST repressor activity is CC associated with progressive hearing loss and deafness. CC {ECO:0000269|PubMed:29961578}. CC -!- DISEASE: Deafness, autosomal dominant, 27 (DFNA27) [MIM:612431]: A form CC of non-syndromic deafness characterized by postlingual, progressive, CC moderate to profound sensorineural hearing loss. CC {ECO:0000269|PubMed:29961578}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. An intronic CC variant that affects alternative splicing of REST and inactivation of CC REST repressor activity fully segregates with deafness in a 3- CC generation family. {ECO:0000269|PubMed:29961578}. CC -!- MISCELLANEOUS: [Isoform 3]: Produced by SRRM4-dependent alternative CC splicing in neurons and inner ear hair cells (By similarity). Lacks the CC four C-terminal zinc fingers and the RCOR1 corepressor interaction site CC found in full length REST isoform 1, which are required for full DNA- CC binding and repressive activity (PubMed:11741002). CC {ECO:0000250|UniProtKB:Q8VIG1, ECO:0000269|PubMed:11741002}. CC -!- CAUTION: [Isoform 3]: Controversial data exists concerning the CC repressor activity of isoform 3. A study showed that isoform 3 exhibits CC weak repressor activity of a NRSE motif-containing reporter construct CC (PubMed:11779185). Another report, however, does not observe any CC isoform 3 transcriptional repressor activity of a NRSE motif-containing CC reporter construct (PubMed:11741002). Controversial data also exists CC regarding the function of isoform 3 on the negative regulation of CC isoform 1. It was shown that isoform 3 negatively regulates the CC repressor activity of isoform 1 by binding to isoform 1, thereby CC preventing its binding to NRSE and leading to derepression of target CC genes (PubMed:11779185). Another study, however, did not observe any CC inhibitory activity of isoform 3 on the isoform 1 transcriptional CC repressor activity (PubMed:11741002). {ECO:0000269|PubMed:11741002, CC ECO:0000269|PubMed:11779185}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA98503.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=AAC50114.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAC50115.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH38985.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; CC Sequence=BAD92987.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/44266/REST"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U22314; AAB17211.1; -; mRNA. DR EMBL; U13877; AAC50114.1; ALT_INIT; mRNA. DR EMBL; U13879; AAC50115.1; ALT_INIT; mRNA. DR EMBL; U22680; AAA98503.1; ALT_FRAME; mRNA. DR EMBL; AB209750; BAD92987.1; ALT_INIT; mRNA. DR EMBL; AC069307; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471057; EAX05517.1; -; Genomic_DNA. DR EMBL; BC038985; AAH38985.1; ALT_SEQ; mRNA. DR EMBL; BC132859; AAI32860.1; -; mRNA. DR EMBL; BC136491; AAI36492.1; -; mRNA. DR CCDS; CCDS3509.1; -. [Q13127-1] DR PIR; A56138; A56138. DR PIR; I38754; I38754. DR PIR; I38755; I38755. DR RefSeq; NP_001180437.1; NM_001193508.2. [Q13127-1] DR RefSeq; NP_001350382.1; NM_001363453.3. [Q13127-1] DR RefSeq; NP_005603.3; NM_005612.4. [Q13127-1] DR PDB; 2CZY; NMR; -; B=43-57. DR PDB; 6DU2; X-ray; 2.50 A; C/D=858-869. DR PDB; 6DU3; X-ray; 2.58 A; C/D=858-869. DR PDBsum; 2CZY; -. DR PDBsum; 6DU2; -. DR PDBsum; 6DU3; -. DR AlphaFoldDB; Q13127; -. DR BMRB; Q13127; -. DR SMR; Q13127; -. DR BioGRID; 111910; 267. DR CORUM; Q13127; -. DR DIP; DIP-35264N; -. DR FunCoup; Q13127; 4087. DR IntAct; Q13127; 20. DR MINT; Q13127; -. DR STRING; 9606.ENSP00000311816; -. DR GlyGen; Q13127; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q13127; -. DR PhosphoSitePlus; Q13127; -. DR BioMuta; REST; -. DR DMDM; 296452989; -. DR jPOST; Q13127; -. DR MassIVE; Q13127; -. DR PaxDb; 9606-ENSP00000311816; -. DR PeptideAtlas; Q13127; -. DR ProteomicsDB; 59175; -. [Q13127-1] DR ProteomicsDB; 59176; -. [Q13127-2] DR ProteomicsDB; 59177; -. [Q13127-3] DR ProteomicsDB; 59178; -. [Q13127-4] DR Pumba; Q13127; -. DR Antibodypedia; 1755; 291 antibodies from 38 providers. DR DNASU; 5978; -. DR Ensembl; ENST00000309042.12; ENSP00000311816.7; ENSG00000084093.20. [Q13127-1] DR Ensembl; ENST00000675105.1; ENSP00000502313.1; ENSG00000084093.20. [Q13127-1] DR GeneID; 5978; -. DR KEGG; hsa:5978; -. DR MANE-Select; ENST00000309042.12; ENSP00000311816.7; NM_005612.5; NP_005603.3. DR UCSC; uc003hch.4; human. [Q13127-1] DR AGR; HGNC:9966; -. DR ClinPGx; PA34334; -. DR CTD; 5978; -. DR DisGeNET; 5978; -. DR GeneCards; REST; -. DR HGNC; HGNC:9966; REST. DR HPA; ENSG00000084093; Low tissue specificity. DR MalaCards; REST; -. DR MIM; 600571; gene. DR MIM; 612431; phenotype. DR MIM; 616806; phenotype. DR MIM; 617626; phenotype. DR OpenTargets; ENSG00000084093; -. DR Orphanet; 2024; Hereditary gingival fibromatosis. DR Orphanet; 654; Nephroblastoma. DR VEuPathDB; HostDB:ENSG00000084093; -. DR eggNOG; KOG1721; Eukaryota. DR GeneTree; ENSGT00940000155341; -. DR HOGENOM; CLU_009801_2_0_1; -. DR InParanoid; Q13127; -. DR OrthoDB; 427030at2759; -. DR PAN-GO; Q13127; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q13127; -. DR PathwayCommons; Q13127; -. DR Reactome; R-HSA-3214815; HDACs deacetylate histones. DR Reactome; R-HSA-8943724; Regulation of PTEN gene transcription. DR Reactome; R-HSA-9031628; NGF-stimulated transcription. DR Reactome; R-HSA-9679191; Potential therapeutics for SARS. DR Reactome; R-HSA-9768777; Regulation of NPAS4 gene transcription. DR SignaLink; Q13127; -. DR SIGNOR; Q13127; -. DR Agora; ENSG00000084093; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 5978; 49 hits in 1187 CRISPR screens. DR ChiTaRS; REST; human. DR GeneWiki; RE1-silencing_transcription_factor; -. DR GenomeRNAi; 5978; -. DR Pharos; Q13127; Tbio. DR PRO; PR:Q13127; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; Q13127; protein. DR Bgee; ENSG00000084093; Expressed in primordial germ cell in gonad and 209 other cell types or tissues. DR ExpressionAtlas; Q13127; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0017053; C:transcription repressor complex; IDA:UniProtKB. DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB. DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:0000979; F:RNA polymerase II core promoter sequence-specific DNA binding; IEA:Ensembl. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:UniProtKB. DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW. DR GO; GO:0060088; P:auditory receptor cell stereocilium organization; ISS:UniProtKB. DR GO; GO:0060379; P:cardiac muscle cell myoblast differentiation; ISS:UniProtKB. DR GO; GO:0071257; P:cellular response to electrical stimulus; IMP:UniProtKB. DR GO; GO:0071385; P:cellular response to glucocorticoid stimulus; IDA:UniProtKB. DR GO; GO:0033554; P:cellular response to stress; IEA:Ensembl. DR GO; GO:0006338; P:chromatin remodeling; ISS:UniProtKB. DR GO; GO:0050910; P:detection of mechanical stimulus involved in sensory perception of sound; ISS:UniProtKB. DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IEA:Ensembl. DR GO; GO:0043922; P:host-mediated suppression of viral transcription; IDA:UniProtKB. DR GO; GO:0099563; P:modification of synaptic structure; ISS:UniProtKB. DR GO; GO:0032348; P:negative regulation of aldosterone biosynthetic process; IMP:UniProtKB. DR GO; GO:2000798; P:negative regulation of amniotic stem cell differentiation; IMP:UniProtKB. DR GO; GO:0045955; P:negative regulation of calcium ion-dependent exocytosis; ISS:UniProtKB. DR GO; GO:2000065; P:negative regulation of cortisol biosynthetic process; IMP:UniProtKB. DR GO; GO:2000706; P:negative regulation of dense core granule biogenesis; ISS:UniProtKB. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010629; P:negative regulation of gene expression; ISS:UniProtKB. DR GO; GO:0046676; P:negative regulation of insulin secretion; IMP:UniProtKB. DR GO; GO:2000740; P:negative regulation of mesenchymal stem cell differentiation; IMP:UniProtKB. DR GO; GO:1902894; P:negative regulation of miRNA transcription; IMP:BHF-UCL. DR GO; GO:0050768; P:negative regulation of neurogenesis; ISS:UniProtKB. DR GO; GO:0045665; P:negative regulation of neuron differentiation; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0050877; P:nervous system process; IMP:UniProtKB. DR GO; GO:0050885; P:neuromuscular process controlling balance; ISS:UniProtKB. DR GO; GO:0097150; P:neuronal stem cell population maintenance; ISS:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; ISS:UniProtKB. DR GO; GO:0045666; P:positive regulation of neuron differentiation; ISS:UniProtKB. DR GO; GO:0043068; P:positive regulation of programmed cell death; ISS:UniProtKB. DR GO; GO:1902459; P:positive regulation of stem cell population maintenance; IDA:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0000381; P:regulation of alternative mRNA splicing, via spliceosome; ISS:UniProtKB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0045667; P:regulation of osteoblast differentiation; ISS:UniProtKB. DR GO; GO:0001666; P:response to hypoxia; IDA:UniProtKB. DR GO; GO:0002931; P:response to ischemia; ISS:UniProtKB. DR GO; GO:0035019; P:somatic stem cell population maintenance; ISS:UniProtKB. DR FunFam; 3.30.160.60:FF:002187; RE1-silencing transcription factor; 1. DR FunFam; 3.30.160.60:FF:000448; RE1-silencing transcription factor A; 1. DR FunFam; 3.30.160.60:FF:000662; RE1-silencing transcription factor A; 1. DR FunFam; 3.30.160.60:FF:000805; RE1-silencing transcription factor B; 1. DR FunFam; 3.30.160.60:FF:000952; RE1-silencing transcription factor B; 1. DR Gene3D; 3.30.160.60; Classic Zinc Finger; 5. DR IDEAL; IID00169; -. DR InterPro; IPR057281; Zfn-C2H2_REST. DR InterPro; IPR050688; Zinc_finger/UBP_domain. DR InterPro; IPR036236; Znf_C2H2_sf. DR InterPro; IPR013087; Znf_C2H2_type. DR PANTHER; PTHR24403:SF102; RE1-SILENCING TRANSCRIPTION FACTOR; 1. DR PANTHER; PTHR24403; ZINC FINGER PROTEIN; 1. DR Pfam; PF00096; zf-C2H2; 1. DR Pfam; PF24540; zf-C2H2_REST; 1. DR SMART; SM00355; ZnF_C2H2; 9. DR SUPFAM; SSF57667; beta-beta-alpha zinc fingers; 3. DR PROSITE; PS00028; ZINC_FINGER_C2H2_1; 1. DR PROSITE; PS50157; ZINC_FINGER_C2H2_2; 6. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Deafness; Disease variant; KW Metal-binding; Non-syndromic deafness; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; Repressor; KW Transcription; Transcription regulation; Ubl conjugation; Zinc; KW Zinc-finger. FT CHAIN 1..1097 FT /note="RE1-silencing transcription factor" FT /id="PRO_0000269547" FT ZN_FING 159..181 FT /note="C2H2-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 216..238 FT /note="C2H2-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 248..270 FT /note="C2H2-type 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 276..298 FT /note="C2H2-type 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 304..326 FT /note="C2H2-type 5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 332..355 FT /note="C2H2-type 6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 361..383 FT /note="C2H2-type 7" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 389..412 FT /note="C2H2-type 8" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 1060..1082 FT /note="C2H2-type 9" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT REGION 32..122 FT /note="Interaction with SIN3A" FT /evidence="ECO:0000269|PubMed:10734093" FT REGION 43..57 FT /note="Interaction with SIN3B" FT /evidence="ECO:0000269|PubMed:16288918" FT REGION 83..103 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 127..159 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 145..418 FT /note="Interaction with ZFP90" FT /evidence="ECO:0000269|PubMed:21284946" FT REGION 201..212 FT /note="Required for binding to the neuron-restrictive FT silencer element" FT /evidence="ECO:0000250|UniProtKB:Q8VIG1" FT REGION 452..642 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 774..837 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 853..938 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 961..1049 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1009..1087 FT /note="Interaction with RCOR1" FT /evidence="ECO:0000269|PubMed:10449787" FT COMPBIAS 86..96 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 452..479 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 480..490 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 495..504 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 559..570 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 577..593 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 803..836 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 913..930 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 864 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 971 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O54963" FT VAR_SEQ 301..313 FT /note="ERPYKCELCPYSS -> KRSFLVHKFSSLF (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7871435" FT /id="VSP_022064" FT VAR_SEQ 304..326 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_022067" FT VAR_SEQ 314..1097 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:7871435" FT /id="VSP_022065" FT VAR_SEQ 329 FT /note="E -> W (in isoform 3)" FT /evidence="ECO:0000305" FT /id="VSP_022066" FT VAR_SEQ 330..1097 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000305" FT /id="VSP_022068" FT VARIANT 160 FT /note="R -> P (in WT6; inhibits transcriptional repression FT activity)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076333" FT VARIANT 290 FT /note="N -> Y (in WT6; inhibits transcriptional repression FT activity)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076334" FT VARIANT 322 FT /note="H -> R (in WT6; inhibits transcriptional repression FT activity; dbSNP:rs869025312)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076335" FT VARIANT 412 FT /note="H -> Q (in WT6)" FT /evidence="ECO:0000269|PubMed:26551668" FT /id="VAR_076336" FT VARIANT 437..1097 FT /note="Missing (in GINGF5)" FT /evidence="ECO:0000269|PubMed:28686854" FT /id="VAR_079529" FT VARIANT 626 FT /note="V -> I (in dbSNP:rs2228991)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_029795" FT VARIANT 692 FT /note="E -> D (in dbSNP:rs2227902)" FT /id="VAR_029796" FT VARIANT 762 FT /note="K -> Q (in dbSNP:rs2227903)" FT /id="VAR_029797" FT VARIANT 797 FT /note="P -> L (in dbSNP:rs3796529)" FT /evidence="ECO:0000269|PubMed:8568247" FT /id="VAR_029798" FT MUTAGEN 91 FT /note="E->G: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 313 FT /note="S->A: Lack of deubiquitination by USP7." FT /evidence="ECO:0000269|PubMed:21258371" FT MUTAGEN 420 FT /note="M->T: Inhibits transcriptional repression activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 512..522 FT /note="KFSKTKKSKRK->AFSKTADSMDA: No effect on nuclear FT localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 512..522 FT /note="KFSKTKKSKRK->GS: Reduced nuclear localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 512..522 FT /note="Missing: No effect on nuclear localization." FT /evidence="ECO:0000269|PubMed:16442230" FT MUTAGEN 593 FT /note="S->N: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 642 FT /note="A->T: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 918 FT /note="H->Y: Does not change transcriptional repression FT activity." FT /evidence="ECO:0000269|PubMed:26551668" FT MUTAGEN 1009..1013 FT /note="EGIHS->AGIHA: Loss of interaction with BTRC. Reduced FT ubiquitination. Decreased proteasomal degradation in G2. FT Decreased average time from nuclear envelope breakdown to FT anaphase onset. Increased number of lagging chromosomes and FT chromosome bridges in anaphase and prematurely separated FT sister chromatids. Reduced MAD2 levels." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1009 FT /note="E->A: Loss of interaction with BTRC." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1013 FT /note="S->A: Loss of interaction with BTRC." FT /evidence="ECO:0000269|PubMed:18354482" FT MUTAGEN 1042 FT /note="S->A: No impact on deubiquitination by USP7." FT /evidence="ECO:0000269|PubMed:21258371" FT CONFLICT 295 FT /note="V -> L (in Ref. 2; AAC50114)" FT /evidence="ECO:0000305" FT CONFLICT 596..599 FT /note="PQKE -> SRNS (in Ref. 2; AAC50115)" FT /evidence="ECO:0000305" FT CONFLICT 630 FT /note="P -> L (in Ref. 1; AAB17211)" FT /evidence="ECO:0000305" FT HELIX 44..55 FT /evidence="ECO:0007829|PDB:2CZY" SQ SEQUENCE 1097 AA; 121872 MW; EBC652EED19CA161 CRC64; MATQVMGQSS GGGGLFTSSG NIGMALPNDM YDLHDLSKAE LAAPQLIMLA NVALTGEVNG SCCDYLVGEE RQMAELMPVG DNNFSDSEEG EGLEESADIK GEPHGLENME LRSLELSVVE PQPVFEASGA PDIYSSNKDL PPETPGAEDK GKSSKTKPFR CKPCQYEAES EEQFVHHIRV HSAKKFFVEE SAEKQAKARE SGSSTAEEGD FSKGPIRCDR CGYNTNRYDH YTAHLKHHTR AGDNERVYKC IICTYTTVSE YHWRKHLRNH FPRKVYTCGK CNYFSDRKNN YVQHVRTHTG ERPYKCELCP YSSSQKTHLT RHMRTHSGEK PFKCDQCSYV ASNQHEVTRH ARQVHNGPKP LNCPHCDYKT ADRSNFKKHV ELHVNPRQFN CPVCDYAASK KCNLQYHFKS KHPTCPNKTM DVSKVKLKKT KKREADLPDN ITNEKTEIEQ TKIKGDVAGK KNEKSVKAEK RDVSKEKKPS NNVSVIQVTT RTRKSVTEVK EMDVHTGSNS EKFSKTKKSK RKLEVDSHSL HGPVNDEESS TKKKKKVESK SKNNSQEVPK GDSKVEENKK QNTCMKKSTK KKTLKNKSSK KSSKPPQKEP VEKGSAQMDP PQMGPAPTEA VQKGPVQVEP PPPMEHAQME GAQIRPAPDE PVQMEVVQEG PAQKELLPPV EPAQMVGAQI VLAHMELPPP METAQTEVAQ MGPAPMEPAQ MEVAQVESAP MQVVQKEPVQ MELSPPMEVV QKEPVQIELS PPMEVVQKEP VKIELSPPIE VVQKEPVQME LSPPMGVVQK EPAQREPPPP REPPLHMEPI SKKPPLRKDK KEKSNMQSER ARKEQVLIEV GLVPVKDSWL LKESVSTEDL SPPSPPLPKE NLREEASGDQ KLLNTGEGNK EAPLQKVGAE EADESLPGLA ANINESTHIS SSGQNLNTPE GETLNGKHQT DSIVCEMKMD TDQNTRENLT GINSTVEEPV SPMLPPSAVE EREAVSKTAL ASPPATMAAN ESQEIDEDEG IHSHEGSDLS DNMSEGSDDS GLHGARPVPQ ESSRKNAKEA LAVKAAKGDF VCIFCDRSFR KGKDYSKHLN RHLVNVYYLE EAAQGQE // ID RIR2B_HUMAN Reviewed; 351 AA. AC Q7LG56; B4E2N4; Q17R22; Q75PQ6; Q75PQ7; Q75PY8; Q75PY9; Q86YE3; Q9NPD6; AC Q9NTD8; Q9NUW3; DT 21-MAR-2006, integrated into UniProtKB/Swiss-Prot. DT 05-JUL-2004, sequence version 1. DT 28-JAN-2026, entry version 197. DE RecName: Full=Ribonucleoside-diphosphate reductase subunit M2 B; DE EC=1.17.4.1; DE AltName: Full=TP53-inducible ribonucleotide reductase M2 B; DE AltName: Full=p53-inducible ribonucleotide reductase small subunit 2-like protein; DE Short=p53R2; GN Name=RRM2B; Synonyms=P53R2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), FUNCTION, AND RP INDUCTION. RX PubMed=10716435; DOI=10.1038/35003506; RA Tanaka H., Arakawa H., Yamaguchi T., Shiraishi K., Fukuda S., Matsui K., RA Takei Y., Nakamura Y.; RT "A ribonucleotide reductase gene involved in a p53-dependent cell-cycle RT checkpoint for DNA damage."; RL Nature 404:42-49(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 4 AND 5). RA Ugai H., Yokoyama K.K.; RT "Homo sapiens p53-inducible ribonucleotide reductase small subunit 2 RT splicing variants."; RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND NUCLEOTIDE SEQUENCE RP [LARGE SCALE MRNA] OF 1-351 (ISOFORM 6). RC TISSUE=Placenta, and Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Amygdala; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16421571; DOI=10.1038/nature04406; RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., RA Platzer M., Shimizu N., Lander E.S.; RT "DNA sequence and analysis of human chromosome 8."; RL Nature 439:331-335(2006). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain, and Eye; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP FUNCTION, AND SUBUNIT. RX PubMed=11517226; DOI=10.1074/jbc.m106088200; RA Guittet O., Haakansson P., Voevodskaya N., Fridd S., Graeslund A., RA Arakawa H., Nakamura Y., Thelander L.; RT "Mammalian p53R2 protein forms an active ribonucleotide reductase in vitro RT with the R1 protein, which is expressed both in resting cells in response RT to DNA damage and in proliferating cells."; RL J. Biol. Chem. 276:40647-40651(2001). RN [10] RP FUNCTION, SUBCELLULAR LOCATION, AND VARIANT LEU-115. RX PubMed=11719458; RA Yamaguchi T., Matsuda K., Sagiya Y., Iwadate M., Fujino M.A., Nakamura Y., RA Arakawa H.; RT "p53R2-dependent pathway for DNA synthesis in a p53-regulated cell cycle RT checkpoint."; RL Cancer Res. 61:8256-8262(2001). RN [11] RP SUBCELLULAR LOCATION, AND INTERACTION WITH TP53 AND RRM1. RX PubMed=12615712; RA Xue L., Zhou B., Liu X., Qiu W., Jin Z., Yen Y.; RT "Wild-type p53 regulates human ribonucleotide reductase by protein-protein RT interaction with p53R2 as well as hRRM2 subunits."; RL Cancer Res. 63:980-986(2003). RN [12] RP TISSUE SPECIFICITY. RX PubMed=14583450; RA Zhou B., Liu X., Mo X., Xue L., Darwish D., Qiu W., Shih J., Hwu E.B., RA Luh F., Yen Y.; RT "The human ribonucleotide reductase subunit hRRM2 complements p53R2 in RT response to UV-induced DNA repair in cells with mutant p53."; RL Cancer Res. 63:6583-6594(2003). RN [13] RP CATALYTIC ACTIVITY, AND SUBUNIT. RX PubMed=16376858; DOI=10.1016/j.bbrc.2005.12.019; RA Qiu W., Zhou B., Darwish D., Shao J., Yen Y.; RT "Characterization of enzymatic properties of human ribonucleotide reductase RT holoenzyme reconstituted in vitro from hRRM1, hRRM2, and p53R2 subunits."; RL Biochem. Biophys. Res. Commun. 340:428-434(2006). RN [14] RP INVOLVEMENT IN PEOA5. RX PubMed=19664747; DOI=10.1016/j.ajhg.2009.07.009; RA Tyynismaa H., Ylikallio E., Patel M., Molnar M.J., Haller R.G., RA Suomalainen A.; RT "A heterozygous truncating mutation in RRM2B causes autosomal-dominant RT progressive external ophthalmoplegia with multiple mtDNA deletions."; RL Am. J. Hum. Genet. 85:290-295(2009). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [16] RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) IN COMPLEX WITH IRON IONS, AND RP COFACTOR. RX PubMed=19728742; DOI=10.1021/bi9001425; RA Smith P., Zhou B., Ho N., Yuan Y.C., Su L., Tsai S.C., Yen Y.; RT "2.6 A X-ray crystal structure of human p53R2, a p53-inducible RT ribonucleotide reductase."; RL Biochemistry 48:11134-11141(2009). RN [17] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 20-322 IN COMPLEX WITH IRON IONS. RG Structural genomics consortium (SGC); RT "Human ribonucleotide reductase, subunit M2 B."; RL Submitted (FEB-2009) to the PDB data bank. RN [18] RP VARIANTS MTDPS8A ARG-64; GLU-85 DEL; GLY-194; LYS-194 AND PHE-236. RX PubMed=17486094; DOI=10.1038/ng2040; RA Bourdon A., Minai L., Serre V., Jais J.-P., Sarzi E., Aubert S., RA Chretien D., de Lonlay P., Paquis-Flucklinger V., Arakawa H., Nakamura Y., RA Munnich A., Roetig A.; RT "Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase RT (p53R2), causes severe mitochondrial DNA depletion."; RL Nat. Genet. 39:776-780(2007). RN [19] RP VARIANTS MTDPS8A SER-224; ILE-282 AND VAL-317. RX PubMed=18504129; DOI=10.1016/j.nmd.2008.04.006; RA Bornstein B., Area E., Flanigan K.M., Ganesh J., Jayakar P., Swoboda K.J., RA Coku J., Naini A., Shanske S., Tanji K., Hirano M., DiMauro S.; RT "Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene."; RL Neuromuscul. Disord. 18:453-459(2008). RN [20] RP VARIANTS MTDPS8B HIS-110 AND HIS-121. RX PubMed=19667227; DOI=10.1001/archneurol.2009.139; RA Shaibani A., Shchelochkov O.A., Zhang S., Katsonis P., Lichtarge O., RA Wong L.J., Shinawi M.; RT "Mitochondrial neurogastrointestinal encephalopathy due to mutations in RT RRM2B."; RL Arch. Neurol. 66:1028-1032(2009). RN [21] RP VARIANT SER-33. RX PubMed=26741492; DOI=10.1371/journal.pgen.1005679; RA Kohda M., Tokuzawa Y., Kishita Y., Nyuzuki H., Moriyama Y., Mizuno Y., RA Hirata T., Yatsuka Y., Yamashita-Sugahara Y., Nakachi Y., Kato H., RA Okuda A., Tamaru S., Borna N.N., Banshoya K., Aigaki T., Sato-Miyata Y., RA Ohnuma K., Suzuki T., Nagao A., Maehata H., Matsuda F., Higasa K., RA Nagasaki M., Yasuda J., Yamamoto M., Fushimi T., Shimura M., RA Kaiho-Ichimoto K., Harashima H., Yamazaki T., Mori M., Murayama K., RA Ohtake A., Okazaki Y.; RT "A comprehensive genomic analysis reveals the genetic landscape of RT mitochondrial respiratory chain complex deficiencies."; RL PLoS Genet. 12:E1005679-E1005679(2016). RN [22] RP VARIANT RCDFRD ASP-262, AND INVOLVEMENT IN RCDFRD. RX PubMed=32827185; DOI=10.1002/humu.24094; RA Roberts L., Julius S., Dawlat S., Yildiz S., Rebello G., Meldau S., RA Pillay K., Esterhuizen A., Vorster A., Benefeld G., da Rocha J., RA Beighton P., Sellars S.L., Thandrayen K., Pettifor J.M., Ramesar R.S.; RT "Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss RT caused by a mutation in RRM2B."; RL Hum. Mutat. 41:1871-1876(2020). CC -!- FUNCTION: Plays a pivotal role in cell survival by repairing damaged CC DNA in a p53/TP53-dependent manner. Supplies deoxyribonucleotides for CC DNA repair in cells arrested at G1 or G2. Contains an iron-tyrosyl free CC radical center required for catalysis. Forms an active ribonucleotide CC reductase (RNR) complex with RRM1 which is expressed both in resting CC and proliferating cells in response to DNA damage. CC {ECO:0000269|PubMed:10716435, ECO:0000269|PubMed:11517226, CC ECO:0000269|PubMed:11719458}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a 2'-deoxyribonucleoside 5'-diphosphate + [thioredoxin]- CC disulfide + H2O = a ribonucleoside 5'-diphosphate + [thioredoxin]- CC dithiol; Xref=Rhea:RHEA:23252, Rhea:RHEA-COMP:10698, Rhea:RHEA- CC COMP:10700, ChEBI:CHEBI:15377, ChEBI:CHEBI:29950, ChEBI:CHEBI:50058, CC ChEBI:CHEBI:57930, ChEBI:CHEBI:73316; EC=1.17.4.1; CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10014, CC ECO:0000269|PubMed:16376858}; CC -!- COFACTOR: CC Name=Fe cation; Xref=ChEBI:CHEBI:24875; CC Evidence={ECO:0000269|PubMed:19728742}; CC Note=Binds 2 iron ions per subunit. {ECO:0000269|PubMed:19728742}; CC -!- SUBUNIT: Heterotetramer with large (RRM1) subunit. Interacts with CC p53/TP53. Interacts with RRM1 in response to DNA damage. CC {ECO:0000269|PubMed:11517226, ECO:0000269|PubMed:12615712, CC ECO:0000269|PubMed:16376858, ECO:0000269|PubMed:19728742, CC ECO:0000269|Ref.17}. CC -!- INTERACTION: CC Q7LG56; Q13315: ATM; NbExp=3; IntAct=EBI-9009083, EBI-495465; CC Q7LG56; Q00987: MDM2; NbExp=2; IntAct=EBI-9009083, EBI-389668; CC Q7LG56; O43929: ORC4; NbExp=4; IntAct=EBI-9009083, EBI-374889; CC Q7LG56; Q9H4P4: RNF41; NbExp=3; IntAct=EBI-9009083, EBI-2130266; CC Q7LG56; Q7LG56: RRM2B; NbExp=3; IntAct=EBI-9009083, EBI-9009083; CC Q7LG56-1; Q00987: MDM2; NbExp=2; IntAct=EBI-15741413, EBI-389668; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Translocates from CC cytoplasm to nucleus in response to DNA damage. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; CC Name=1; CC IsoId=Q7LG56-1; Sequence=Displayed; CC Name=2; Synonyms=Long form; CC IsoId=Q7LG56-2; Sequence=VSP_017670; CC Name=3; Synonyms=Short form gamma; CC IsoId=Q7LG56-3; Sequence=VSP_017669; CC Name=4; Synonyms=Short form beta; CC IsoId=Q7LG56-4; Sequence=VSP_017668; CC Name=5; Synonyms=Short form; CC IsoId=Q7LG56-5; Sequence=VSP_017671, VSP_017672; CC Name=6; CC IsoId=Q7LG56-6; Sequence=VSP_053585; CC -!- TISSUE SPECIFICITY: Widely expressed at a high level in skeletal muscle CC and at a weak level in thymus. Expressed in epithelial dysplasias and CC squamous cell carcinoma. {ECO:0000269|PubMed:14583450}. CC -!- INDUCTION: In response to DNA damage in a wild-type p53/TP53-dependent CC manner. {ECO:0000269|PubMed:10716435}. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 8A (MTDPS8A) CC [MIM:612075]: A disorder due to mitochondrial dysfunction characterized CC by various combinations of neonatal hypotonia, neurological CC deterioration, respiratory distress, lactic acidosis, and renal CC tubulopathy. {ECO:0000269|PubMed:17486094, CC ECO:0000269|PubMed:18504129}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 8B (MTDPS8B) CC [MIM:612075]: A disease due to mitochondrial dysfunction and CC characterized by ophthalmoplegia, ptosis, gastrointestinal dysmotility, CC cachexia, peripheral neuropathy. {ECO:0000269|PubMed:19667227}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 5 (PEOA5) [MIM:613077]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:19664747}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Rod-cone dystrophy, sensorineural deafness, and Fanconi-type CC renal dysfunction (RCDFRD) [MIM:268315]: An autosomal recessive disease CC characterized by visual impairment due to rod-cone dystrophy, CC sensorineural hearing loss, and Fanconi-type renal dysfunction CC resulting in rickets-like skeletal changes. Death may occur in CC childhood or young adulthood due to renal failure. Disease onset is CC before age 5 years. {ECO:0000269|PubMed:32827185}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 5]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the ribonucleoside diphosphate reductase small CC chain family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAG65196.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=EAW91842.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB036063; BAA92434.1; -; mRNA. DR EMBL; AB036532; BAA92493.1; -; Genomic_DNA. DR EMBL; AB163437; BAD11774.1; -; mRNA. DR EMBL; AB163438; BAD11775.1; -; mRNA. DR EMBL; AB166669; BAD12265.1; -; mRNA. DR EMBL; AB166670; BAD12266.1; -; mRNA. DR EMBL; AB166671; BAD12267.1; -; mRNA. DR EMBL; AK001965; BAA92005.1; -; mRNA. DR EMBL; AK304354; BAG65196.1; ALT_INIT; mRNA. DR EMBL; DC308409; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AL137348; CAB70703.2; -; mRNA. DR EMBL; DQ027001; AAY29059.1; -; Genomic_DNA. DR EMBL; AP001328; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP002907; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471060; EAW91842.1; ALT_SEQ; Genomic_DNA. DR EMBL; BC042468; AAH42468.1; -; mRNA. DR EMBL; BC108261; AAI08262.1; -; mRNA. DR EMBL; BC117496; AAI17497.1; -; mRNA. DR EMBL; BC130628; AAI30629.1; -; mRNA. DR CCDS; CCDS34932.1; -. [Q7LG56-1] DR CCDS; CCDS55267.1; -. [Q7LG56-2] DR PIR; T46249; T46249. DR RefSeq; NP_001165948.1; NM_001172477.1. [Q7LG56-6] DR RefSeq; NP_001165949.1; NM_001172478.2. [Q7LG56-2] DR RefSeq; NP_056528.2; NM_015713.4. [Q7LG56-1] DR PDB; 2VUX; X-ray; 2.80 A; A/B=20-322. DR PDB; 3HF1; X-ray; 2.60 A; A/B=1-351. DR PDB; 4DJN; X-ray; 2.20 A; A/B=13-322. DR PDBsum; 2VUX; -. DR PDBsum; 3HF1; -. DR PDBsum; 4DJN; -. DR AlphaFoldDB; Q7LG56; -. DR SMR; Q7LG56; -. DR BioGRID; 119071; 74. DR ComplexPortal; CPX-369; Ribonucleoside-diphosphate reductase RR1 complex, RRM2B variant. DR CORUM; Q7LG56; -. DR DIP; DIP-24264N; -. DR DIP; DIP-48627N; -. DR FunCoup; Q7LG56; 2091. DR IntAct; Q7LG56; 34. DR STRING; 9606.ENSP00000251810; -. DR BindingDB; Q7LG56; -. DR ChEMBL; CHEMBL3301398; -. DR DrugBank; DB00242; Cladribine. DR DrugBank; DB00631; Clofarabine. DR DrugBank; DB12948; Didox. DR GlyGen; Q7LG56; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q7LG56; -. DR PhosphoSitePlus; Q7LG56; -. DR BioMuta; RRM2B; -. DR DMDM; 74727333; -. DR jPOST; Q7LG56; -. DR MassIVE; Q7LG56; -. DR PaxDb; 9606-ENSP00000251810; -. DR PeptideAtlas; Q7LG56; -. DR ProteomicsDB; 5837; -. DR ProteomicsDB; 68860; -. [Q7LG56-1] DR ProteomicsDB; 68861; -. [Q7LG56-2] DR ProteomicsDB; 68862; -. [Q7LG56-3] DR ProteomicsDB; 68863; -. [Q7LG56-4] DR ProteomicsDB; 68864; -. [Q7LG56-5] DR Pumba; Q7LG56; -. DR Antibodypedia; 3483; 343 antibodies from 38 providers. DR DNASU; 50484; -. DR Ensembl; ENST00000251810.8; ENSP00000251810.3; ENSG00000048392.14. [Q7LG56-1] DR Ensembl; ENST00000395912.6; ENSP00000379248.2; ENSG00000048392.14. [Q7LG56-2] DR Ensembl; ENST00000519317.5; ENSP00000430641.1; ENSG00000048392.14. [Q7LG56-3] DR Ensembl; ENST00000519962.5; ENSP00000429140.1; ENSG00000048392.14. [Q7LG56-4] DR Ensembl; ENST00000522394.1; ENSP00000429578.1; ENSG00000048392.14. [Q7LG56-5] DR GeneID; 50484; -. DR KEGG; hsa:50484; -. DR MANE-Select; ENST00000251810.8; ENSP00000251810.3; NM_015713.5; NP_056528.2. DR UCSC; uc003ykn.4; human. [Q7LG56-1] DR AGR; HGNC:17296; -. DR ClinPGx; PA34866; -. DR CTD; 50484; -. DR DisGeNET; 50484; -. DR GeneCards; RRM2B; -. DR GeneReviews; RRM2B; -. DR HGNC; HGNC:17296; RRM2B. DR HPA; ENSG00000048392; Low tissue specificity. DR MalaCards; RRM2B; -. DR MIM; 268315; phenotype. DR MIM; 604712; gene. DR MIM; 612075; phenotype. DR MIM; 613077; phenotype. DR OpenTargets; ENSG00000048392; -. DR Orphanet; 329336; Adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR Orphanet; 480; Kearns-Sayre syndrome. DR Orphanet; 255235; Mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy. DR Orphanet; 298; Mitochondrial neurogastrointestinal encephalomyopathy. DR VEuPathDB; HostDB:ENSG00000048392; -. DR eggNOG; KOG1567; Eukaryota. DR GeneTree; ENSGT00390000013305; -. DR HOGENOM; CLU_035339_2_0_1; -. DR InParanoid; Q7LG56; -. DR OMA; LEPMFLG; -. DR OrthoDB; 10248373at2759; -. DR PAN-GO; Q7LG56; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q7LG56; -. DR BRENDA; 1.17.4.1; 2681. DR PathwayCommons; Q7LG56; -. DR Reactome; R-HSA-499943; Interconversion of nucleotide di- and triphosphates. DR Reactome; R-HSA-5628897; TP53 Regulates Metabolic Genes. DR SignaLink; Q7LG56; -. DR SIGNOR; Q7LG56; -. DR Agora; ENSG00000048392; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 50484; 17 hits in 1170 CRISPR screens. DR ChiTaRS; RRM2B; human. DR EvolutionaryTrace; Q7LG56; -. DR GeneWiki; RRM2B; -. DR GenomeRNAi; 50484; -. DR Pharos; Q7LG56; Tbio. DR PRO; PR:Q7LG56; -. DR Proteomes; UP000005640; Chromosome 8. DR RNAct; Q7LG56; protein. DR Bgee; ENSG00000048392; Expressed in secondary oocyte and 188 other cell types or tissues. DR ExpressionAtlas; Q7LG56; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005739; C:mitochondrion; IEA:GOC. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005971; C:ribonucleoside-diphosphate reductase complex; ISS:ComplexPortal. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0004748; F:ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor; IBA:GO_Central. DR GO; GO:0009265; P:2'-deoxyribonucleotide biosynthetic process; IDA:ComplexPortal. DR GO; GO:0009200; P:deoxyribonucleoside triphosphate metabolic process; IEA:Ensembl. DR GO; GO:0009263; P:deoxyribonucleotide biosynthetic process; IBA:GO_Central. DR GO; GO:0006281; P:DNA repair; IDA:ComplexPortal. DR GO; GO:0000731; P:DNA synthesis involved in DNA repair; NAS:ComplexPortal. DR GO; GO:0001822; P:kidney development; IEA:Ensembl. DR GO; GO:0006264; P:mitochondrial DNA replication; IMP:ComplexPortal. DR GO; GO:1902254; P:negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator; IEA:Ensembl. DR GO; GO:0070318; P:positive regulation of G0 to G1 transition; IDA:ComplexPortal. DR GO; GO:0010971; P:positive regulation of G2/M transition of mitotic cell cycle; IDA:ComplexPortal. DR GO; GO:0003014; P:renal system process; IEA:Ensembl. DR GO; GO:0014075; P:response to amine; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl. DR GO; GO:0009185; P:ribonucleoside diphosphate metabolic process; IDA:ComplexPortal. DR CDD; cd01049; RNRR2; 1. DR FunFam; 1.10.620.20:FF:000004; Ribonucleoside-diphosphate reductase subunit M2 B; 1. DR Gene3D; 1.10.620.20; Ribonucleotide Reductase, subunit A; 1. DR InterPro; IPR009078; Ferritin-like_SF. DR InterPro; IPR012348; RNR-like. DR InterPro; IPR033909; RNR_small. DR InterPro; IPR030475; RNR_small_AS. DR InterPro; IPR000358; RNR_small_fam. DR PANTHER; PTHR23409; RIBONUCLEOSIDE-DIPHOSPHATE REDUCTASE SMALL CHAIN; 1. DR PANTHER; PTHR23409:SF19; RIBONUCLEOSIDE-DIPHOSPHATE REDUCTASE SUBUNIT M2 B; 1. DR Pfam; PF00268; Ribonuc_red_sm; 1. DR SUPFAM; SSF47240; Ferritin-like; 1. DR PROSITE; PS00368; RIBORED_SMALL; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Deafness; KW Deoxyribonucleotide synthesis; Disease variant; DNA damage; DNA repair; KW Iron; Metal-binding; Neuropathy; Nucleus; Oxidoreductase; KW Primary mitochondrial disease; Progressive external ophthalmoplegia; KW Proteomics identification; Reference proteome. FT CHAIN 1..351 FT /note="Ribonucleoside-diphosphate reductase subunit M2 B" FT /id="PRO_0000228150" FT REGION 1..32 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 138 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10014" FT BINDING 100 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="1" FT BINDING 131 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="1" FT BINDING 131 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="2" FT BINDING 134 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="1" FT BINDING 194 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="2" FT BINDING 228 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="2" FT BINDING 231 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="2" FT VAR_SEQ 1..16 FT /note="MGDPERPEAAGLDQDE -> MLLLRLPPHRSHASPLDCKLQDRCRKCYSPRS FT GQACPPALAAAWLRRCERRGGRPRGGRRKELTLGLRPARCSAPGPAKDDAWRPQAG FT (in isoform 6)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_053585" FT VAR_SEQ 17..301 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_017668" FT VAR_SEQ 17..228 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_017669" FT VAR_SEQ 17..68 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_017670" FT VAR_SEQ 42..43 FT /note="FV -> SF (in isoform 5)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_017671" FT VAR_SEQ 44..351 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_017672" FT VARIANT 33 FT /note="P -> S (found in a patient with combined respiratory FT complex deficiencies, muscle weakness and hearing loss; FT uncertain significance; dbSNP:rs387906892)" FT /evidence="ECO:0000269|PubMed:26741492" FT /id="VAR_076280" FT VARIANT 64 FT /note="W -> R (in MTDPS8A; dbSNP:rs515726182)" FT /evidence="ECO:0000269|PubMed:17486094" FT /id="VAR_046217" FT VARIANT 85 FT /note="Missing (in MTDPS8A; dbSNP:rs515726184)" FT /evidence="ECO:0000269|PubMed:17486094" FT /id="VAR_046218" FT VARIANT 110 FT /note="R -> H (in MTDPS8B; dbSNP:rs267607025)" FT /evidence="ECO:0000269|PubMed:19667227" FT /id="VAR_065122" FT VARIANT 115 FT /note="V -> L (in colorectal adenocarcinomas cell line; FT loss of ribonucleotide reductase activity)" FT /evidence="ECO:0000269|PubMed:11719458" FT /id="VAR_025699" FT VARIANT 121 FT /note="R -> H (in MTDPS8B; dbSNP:rs267607024)" FT /evidence="ECO:0000269|PubMed:19667227" FT /id="VAR_065123" FT VARIANT 194 FT /note="E -> G (in MTDPS8A; dbSNP:rs515726191)" FT /evidence="ECO:0000269|PubMed:17486094" FT /id="VAR_046219" FT VARIANT 194 FT /note="E -> K (in MTDPS8A; dbSNP:rs121918308)" FT /evidence="ECO:0000269|PubMed:17486094" FT /id="VAR_046220" FT VARIANT 224 FT /note="I -> S (in MTDPS8A; without tubulopathy; FT dbSNP:rs515726196)" FT /evidence="ECO:0000269|PubMed:18504129" FT /id="VAR_046221" FT VARIANT 236 FT /note="C -> F (in MTDPS8A; dbSNP:rs121918309)" FT /evidence="ECO:0000269|PubMed:17486094" FT /id="VAR_046222" FT VARIANT 262 FT /note="E -> D (in RCDFRD; dbSNP:rs1810682433)" FT /evidence="ECO:0000269|PubMed:32827185" FT /id="VAR_086956" FT VARIANT 282 FT /note="M -> I (in MTDPS8A; without tubulopathy; FT dbSNP:rs182614164)" FT /evidence="ECO:0000269|PubMed:18504129" FT /id="VAR_046223" FT VARIANT 317 FT /note="L -> V (in MTDPS8A; without tubulopathy; FT dbSNP:rs515726198)" FT /evidence="ECO:0000269|PubMed:18504129" FT /id="VAR_046224" FT CONFLICT 277 FT /note="M -> V (in Ref. 3; BAA92005)" FT /evidence="ECO:0000305" FT HELIX 29..31 FT /evidence="ECO:0007829|PDB:4DJN" FT TURN 33..35 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 37..39 FT /evidence="ECO:0007829|PDB:4DJN" FT STRAND 42..44 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 50..61 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 66..68 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 74..78 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 83..109 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 111..114 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 118..145 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 149..156 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 158..161 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 163..177 FT /evidence="ECO:0007829|PDB:4DJN" FT STRAND 179..181 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 183..195 FT /evidence="ECO:0007829|PDB:4DJN" FT TURN 196..198 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 199..210 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 215..240 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 248..267 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 272..275 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 279..296 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 310..312 FT /evidence="ECO:0007829|PDB:4DJN" SQ SEQUENCE 351 AA; 40737 MW; 6D008687EEF40994 CRC64; MGDPERPEAA GLDQDERSSS DTNESEIKSN EEPLLRKSSR RFVIFPIQYP DIWKMYKQAQ ASFWTAEEVD LSKDLPHWNK LKADEKYFIS HILAFFAASD GIVNENLVER FSQEVQVPEA RCFYGFQILI ENVHSEMYSL LIDTYIRDPK KREFLFNAIE TMPYVKKKAD WALRWIADRK STFGERVVAF AAVEGVFFSG SFAAIFWLKK RGLMPGLTFS NELISRDEGL HCDFACLMFQ YLVNKPSEER VREIIVDAVK IEQEFLTEAL PVGLIGMNCI LMKQYIEFVA DRLLVELGFS KVFQAENPFD FMENISLEGK TNFFEKRVSE YQRFAVMAET TDNVFTLDAD F //