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 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 NGBR_HUMAN Reviewed; 293 AA. AC Q96E22; B2RWQ4; O00251; DT 23-JAN-2007, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 28-JAN-2026, entry version 178. DE RecName: Full=Dehydrodolichyl diphosphate synthase complex subunit NUS1 {ECO:0000305}; DE EC=2.5.1.87 {ECO:0000269|PubMed:25066056, ECO:0000269|PubMed:28842490}; DE AltName: Full=Cis-prenyltransferase subunit NgBR {ECO:0000303|PubMed:28842490}; DE AltName: Full=Nogo-B receptor {ECO:0000303|PubMed:16835300}; DE Short=NgBR {ECO:0000303|PubMed:16835300, ECO:0000303|PubMed:28842490}; DE AltName: Full=Nuclear undecaprenyl pyrophosphate synthase 1 homolog {ECO:0000305}; GN Name=NUS1 {ECO:0000303|PubMed:28842490, ECO:0000312|HGNC:HGNC:21042}; GN Synonyms=C6orf68, NGBR; 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 [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 [2] 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 [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lymph, Muscle, 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 [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 171-293, AND VARIANTS ARG-216 AND LYS-219. RX PubMed=9294218; DOI=10.1073/pnas.94.19.10373; RA Still I.H., Vince P., Cowell J.K.; RT "Direct isolation of human transcribed sequences from yeast artificial RT chromosomes through the application of RNA fingerprinting."; RL Proc. Natl. Acad. Sci. U.S.A. 94:10373-10378(1997). RN [5] RP FUNCTION, AND LACK OF TRANSFERASE ACTIVITY. RX PubMed=16835300; DOI=10.1073/pnas.0602427103; RA Miao R.Q., Gao Y., Harrison K.D., Prendergast J., Acevedo L.M., Yu J., RA Hu F., Strittmatter S.M., Sessa W.C.; RT "Identification of a receptor necessary for Nogo-B stimulated chemotaxis RT and morphogenesis of endothelial cells."; RL Proc. Natl. Acad. Sci. U.S.A. 103:10997-11002(2006). RN [6] RP SUBCELLULAR LOCATION, AND INTERACTION WITH NPC2. RX PubMed=19723497; DOI=10.1016/j.cmet.2009.07.003; RA Harrison K.D., Miao R.Q., Fernandez-Hernando C., Suarez Y., Davalos A., RA Sessa W.C.; RT "Nogo-B receptor stabilizes Niemann-Pick type C2 protein and regulates RT intracellular cholesterol trafficking."; RL Cell Metab. 10:208-218(2009). RN [7] RP FUNCTION IN DOLICHOL BIOSYNTHESIS, SUBCELLULAR LOCATION, GLYCOSYLATION AT RP ASN-144 AND ASN-271, AND INTERACTION WITH DHDDS. RX PubMed=21572394; DOI=10.1038/emboj.2011.147; RA Harrison K.D., Park E.J., Gao N., Kuo A., Rush J.S., Waechter C.J., RA Lehrman M.A., Sessa W.C.; RT "Nogo-B receptor is necessary for cellular dolichol biosynthesis and RT protein N-glycosylation."; RL EMBO J. 30:2490-2500(2011). RN [8] RP INVOLVEMENT IN CDG1AA, VARIANT CDG1AA HIS-290, CHARACTERIZATION OF VARIANT RP CDG1AA HIS-290, CATALYTIC ACTIVITY, FUNCTION, SUBUNIT, AND PATHWAY. RX PubMed=25066056; DOI=10.1016/j.cmet.2014.06.016; RA Park E.J., Grabinska K.A., Guan Z., Stranecky V., Hartmannova H., RA Hodanova K., Baresova V., Sovova J., Jozsef L., Ondruskova N., RA Hansikova H., Honzik T., Zeman J., Hulkova H., Wen R., Kmoch S., RA Sessa W.C.; RT "Mutation of Nogo-B receptor, a subunit of cis-prenyltransferase, causes a RT congenital disorder of glycosylation."; RL Cell Metab. 20:448-457(2014). RN [9] RP CATALYTIC ACTIVITY, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, RP MUTAGENESIS OF HIS-100; GLY-292 AND LYS-293, ACTIVITY REGULATION, RP CHARACTERIZATION OF VARIANT HIS-290, PATHWAY, AND COFACTOR. RX PubMed=28842490; DOI=10.1074/jbc.m117.806034; RA Grabinska K.A., Edani B.H., Park E.J., Kraehling J.R., Sessa W.C.; RT "A conserved C-terminal RXG motif in the NgBR subunit of cis- RT prenyltransferase is critical for prenyltransferase activity."; RL J. Biol. Chem. 292:17351-17361(2017). RN [10] {ECO:0007744|PDB:6Z1N} RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 79-293 IN COMPLEX WITH DHDDS, RP FUNCTION, PATHWAY, SUBUNIT, AND CHARACTERIZATION OF VARIANT HIS-290. RX PubMed=33077723; DOI=10.1038/s41467-020-18970-z; RA Bar-El M.L., Vankova P., Yeheskel A., Simhaev L., Engel H., Man P., RA Haitin Y., Giladi M.; RT "Structural basis of heterotetrameric assembly and disease mutations in the RT human cis-prenyltransferase complex."; RL Nat. Commun. 11:5273-5273(2020). RN [11] RP X-RAY CRYSTALLOGRAPHY (2.31 ANGSTROMS) OF 79-293 IN COMPLEX WITH DHDDS AND RP ISOPENTENYL DIPHOSPHATE, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, RP SUBUNIT, DOMAIN, MUTAGENESIS OF GLY-196; LYS-197; ILE-200; LEU-226; RP LEU-230; GLY-252; PHE-253 AND PRO-255, AND VARIANT CYS-91. RX PubMed=32817466; DOI=10.1073/pnas.2008381117; RA Edani B.H., Grabinska K.A., Zhang R., Park E.J., Siciliano B., Surmacz L., RA Ha Y., Sessa W.C.; RT "Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex RT reveals insights in regulation of protein glycosylation."; RL Proc. Natl. Acad. Sci. U.S.A. 117:20794-20802(2020). RN [12] {ECO:0007744|PDB:7PAX, ECO:0007744|PDB:7PAY, ECO:0007744|PDB:7PB0, ECO:0007744|PDB:7PB1} RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 79-293 IN COMPLEX WITH DHDDS, AND RP SUBUNIT. RX PubMed=35584224; DOI=10.1126/sciadv.abn1171; RA Giladi M., Lisnyansky Bar-El M., Vankova P., Ferofontov A., Melvin E., RA Alkaderi S., Kavan D., Redko B., Haimov E., Wiener R., Man P., Haitin Y.; RT "Structural basis for long-chain isoprenoid synthesis by cis- RT prenyltransferases."; RL Sci. Adv. 8:eabn1171-eabn1171(2022). RN [13] RP INVOLVEMENT IN MRD55. RX PubMed=29100083; DOI=10.1016/j.ajhg.2017.09.008; RG Deciphering Developmental Disorders Study; RA Hamdan F.F., Myers C.T., Cossette P., Lemay P., Spiegelman D., RA Laporte A.D., Nassif C., Diallo O., Monlong J., Cadieux-Dion M., RA Dobrzeniecka S., Meloche C., Retterer K., Cho M.T., Rosenfeld J.A., Bi W., RA Massicotte C., Miguet M., Brunga L., Regan B.M., Mo K., Tam C., RA Schneider A., Hollingsworth G., FitzPatrick D.R., Donaldson A., Canham N., RA Blair E., Kerr B., Fry A.E., Thomas R.H., Shelagh J., Hurst J.A., RA Brittain H., Blyth M., Lebel R.R., Gerkes E.H., Davis-Keppen L., Stein Q., RA Chung W.K., Dorison S.J., Benke P.J., Fassi E., Corsten-Janssen N., RA Kamsteeg E.J., Mau-Them F.T., Bruel A.L., Verloes A., Ounap K., RA Wojcik M.H., Albert D.V.F., Venkateswaran S., Ware T., Jones D., Liu Y.C., RA Mohammad S.S., Bizargity P., Bacino C.A., Leuzzi V., Martinelli S., RA Dallapiccola B., Tartaglia M., Blumkin L., Wierenga K.J., Purcarin G., RA O'Byrne J.J., Stockler S., Lehman A., Keren B., Nougues M.C., Mignot C., RA Auvin S., Nava C., Hiatt S.M., Bebin M., Shao Y., Scaglia F., Lalani S.R., RA Frye R.E., Jarjour I.T., Jacques S., Boucher R.M., Riou E., Srour M., RA Carmant L., Lortie A., Major P., Diadori P., Dubeau F., D'Anjou G., RA Bourque G., Berkovic S.F., Sadleir L.G., Campeau P.M., Kibar Z., RA Lafreniere R.G., Girard S.L., Mercimek-Mahmutoglu S., Boelman C., RA Rouleau G.A., Scheffer I.E., Mefford H.C., Andrade D.M., Rossignol E., RA Minassian B.A., Michaud J.L.; RT "High rate of recurrent de novo mutations in developmental and epileptic RT encephalopathies."; RL Am. J. Hum. Genet. 101:664-685(2017). RN [14] RP VARIANT 104-VAL--LYS-293 DEL. RX PubMed=33798445; DOI=10.1016/j.ajhg.2021.03.013; RA Courage C., Oliver K.L., Park E.J., Cameron J.M., Grabinska K.A., Muona M., RA Canafoglia L., Gambardella A., Said E., Afawi Z., Baykan B., Brandt C., RA di Bonaventura C., Chew H.B., Criscuolo C., Dibbens L.M., Castellotti B., RA Riguzzi P., Labate A., Filla A., Giallonardo A.T., Berecki G., RA Jackson C.B., Joensuu T., Damiano J.A., Kivity S., Korczyn A., Palotie A., RA Striano P., Uccellini D., Giuliano L., Andermann E., Scheffer I.E., RA Michelucci R., Bahlo M., Franceschetti S., Sessa W.C., Berkovic S.F., RA Lehesjoki A.E.; RT "Progressive myoclonus epilepsies-Residual unsolved cases have marked RT genetic heterogeneity including dolichol-dependent protein glycosylation RT pathway genes."; RL Am. J. Hum. Genet. 108:722-738(2021). CC -!- FUNCTION: With DHDDS, forms the dehydrodolichyl diphosphate synthase CC (DDS) complex, an essential component of the dolichol monophosphate CC (Dol-P) biosynthetic machinery (PubMed:21572394, PubMed:25066056, CC PubMed:28842490, PubMed:32817466, PubMed:33077723). Both subunits CC contribute to enzymatic activity, i.e. condensation of multiple copies CC of isopentenyl pyrophosphate (IPP) to farnesyl pyrophosphate (FPP) to CC produce dehydrodolichyl diphosphate (Dedol-PP), a precursor of dolichol CC phosphate which is utilized as a sugar carrier in protein glycosylation CC in the endoplasmic reticulum (ER) (PubMed:21572394, PubMed:25066056, CC PubMed:28842490, PubMed:32817466, PubMed:33077723). Synthesizes long- CC chain polyprenols, mostly of C95 and C100 chain length CC (PubMed:32817466). Regulates the glycosylation and stability of nascent CC NPC2, thereby promoting trafficking of LDL-derived cholesterol CC (PubMed:21572394). Acts as a specific receptor for the N-terminus of CC Nogo-B, a neural and cardiovascular regulator (PubMed:16835300). CC {ECO:0000269|PubMed:16835300, ECO:0000269|PubMed:21572394, CC ECO:0000269|PubMed:25066056, ECO:0000269|PubMed:28842490, CC ECO:0000269|PubMed:32817466, ECO:0000269|PubMed:33077723}. CC -!- CATALYTIC ACTIVITY: CC Reaction=n isopentenyl diphosphate + (2E,6E)-farnesyl diphosphate = a CC di-trans,poly-cis-polyprenyl diphosphate + n diphosphate; CC Xref=Rhea:RHEA:53008, Rhea:RHEA-COMP:19494, ChEBI:CHEBI:33019, CC ChEBI:CHEBI:128769, ChEBI:CHEBI:136960, ChEBI:CHEBI:175763; CC EC=2.5.1.87; Evidence={ECO:0000269|PubMed:25066056, CC ECO:0000269|PubMed:28842490, ECO:0000269|PubMed:32817466}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:28842490}; CC -!- ACTIVITY REGULATION: Activated by phospholipids including cardiolipin, CC phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and CC phosphatidylserine. {ECO:0000269|PubMed:28842490, CC ECO:0000269|PubMed:32817466}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=11.1 uM for isopentenyl diphosphate {ECO:0000269|PubMed:28842490}; CC KM=0.68 uM for (2E,6E)-farnesyl diphosphate CC {ECO:0000269|PubMed:28842490}; CC Note=Values were measured with the heterodimer. kcat is 0.58 sec(-1) CC with (2E,6E)-farnesyl diphosphate and isopentenyl diphosphate as CC substrates. {ECO:0000269|PubMed:28842490}; CC pH dependence: CC Optimum pH is 8-9. Active from pH 5.5 to 9.3. CC {ECO:0000269|PubMed:28842490}; CC -!- PATHWAY: Protein modification; protein glycosylation. CC {ECO:0000269|PubMed:25066056, ECO:0000269|PubMed:33077723}. CC -!- PATHWAY: Lipid metabolism. {ECO:0000269|PubMed:25066056, CC ECO:0000269|PubMed:28842490}. CC -!- SUBUNIT: The active dehydrodolichyl diphosphate synthase complex is a CC heterotetramer composed of a dimer of heterodimer of DHDDS and NUS1 CC (PubMed:19723497, PubMed:25066056, PubMed:28842490, PubMed:32817466, CC PubMed:33077723, PubMed:35584224). Interacts with NPC2 CC (PubMed:21572394). {ECO:0000269|PubMed:19723497, CC ECO:0000269|PubMed:21572394, ECO:0000269|PubMed:25066056, CC ECO:0000269|PubMed:28842490, ECO:0000269|PubMed:32817466, CC ECO:0000269|PubMed:33077723, ECO:0000269|PubMed:35584224}. CC -!- INTERACTION: CC Q96E22; Q9H7T3: C10orf95; NbExp=3; IntAct=EBI-6949352, EBI-6949335; CC Q96E22; Q86SQ9: DHDDS; NbExp=6; IntAct=EBI-6949352, EBI-26942900; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:19723497, ECO:0000269|PubMed:21572394}; Multi-pass CC membrane protein {ECO:0000303|PubMed:21572394}. Note=Colocalizes with CC Nogo-B during VEGF and wound healing angiogenesis. CC {ECO:0000269|PubMed:19723497}. CC -!- DOMAIN: Contains the RXG motif, which is important for substrate CC binding and prenyltransferase activity. The catalytic site at NUS1- CC DHDDS interface accomodates both the allylic and the homoallylic IPP CC substrates to the S1 and S2 pockets respectively. The beta-phosphate CC groups of IPP substrates form hydrogen bonds with the RXG motif of NUS1 CC and four conserved residues of DHDDS ('Arg-85', 'Arg-205', 'Arg-211' CC and 'Ser-213'), while the allylic isopentenyl group is pointed toward CC the hydrophobic tunnel of the S1 pocket where the product elongation CC occurs. {ECO:0000269|PubMed:32817466}. CC -!- DISEASE: Congenital disorder of glycosylation 1AA (CDG1AA) CC [MIM:617082]: A form of congenital disorder of glycosylation, a CC multisystem disorder caused by a defect in glycoprotein biosynthesis CC and characterized by under-glycosylated serum glycoproteins. Congenital CC disorders of glycosylation result in a wide variety of clinical CC features, such as defects in the nervous system development, CC psychomotor retardation, dysmorphic features, hypotonia, coagulation CC disorders, and immunodeficiency. The broad spectrum of features CC reflects the critical role of N-glycoproteins during embryonic CC development, differentiation, and maintenance of cell functions. CDG1AA CC inheritance is autosomal recessive. {ECO:0000269|PubMed:25066056}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Intellectual developmental disorder, autosomal dominant 55, CC with seizures (MRD55) [MIM:617831]: A form of intellectual disability, CC a disorder characterized by significantly below average general CC intellectual functioning associated with impairments in adaptive CC behavior and manifested during the developmental period. MRD55 patients CC suffer from seizures appearing during the first years of life. CC {ECO:0000269|PubMed:29100083}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: NUS1 seems to exist in two topological orientations, a CC minor glycosylated species with its C-terminus oriented towards the CC lumen regulating NPC2 stability, and a major fraction oriented with its CC C-terminus directed towards the cytosol where it regulates cis-IPTase CC activity. {ECO:0000303|PubMed:21572394}. CC -!- SIMILARITY: Belongs to the UPP synthase family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAB72234.1; Type=Frameshift; 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; Z98172; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL590303; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471051; EAW48201.1; -; Genomic_DNA. DR EMBL; BC013026; AAH13026.1; -; mRNA. DR EMBL; BC063794; AAH63794.1; -; mRNA. DR EMBL; BC066910; AAH66910.1; -; mRNA. DR EMBL; BC110325; AAI10326.1; -; mRNA. DR EMBL; BC150654; AAI50655.1; -; mRNA. DR EMBL; BC150655; AAI50656.1; -; mRNA. DR EMBL; U82319; AAB72234.1; ALT_FRAME; mRNA. DR CCDS; CCDS5118.1; -. DR RefSeq; NP_612468.1; NM_138459.5. DR PDB; 6W2L; X-ray; 2.31 A; B=80-293. DR PDB; 6Z1N; X-ray; 2.30 A; B=73-293. DR PDB; 7PAX; X-ray; 2.00 A; B=73-293. DR PDB; 7PAY; X-ray; 2.40 A; B=73-293. DR PDB; 7PB0; X-ray; 2.30 A; B=73-293. DR PDB; 7PB1; X-ray; 2.59 A; B=73-293. DR PDBsum; 6W2L; -. DR PDBsum; 6Z1N; -. DR PDBsum; 7PAX; -. DR PDBsum; 7PAY; -. DR PDBsum; 7PB0; -. DR PDBsum; 7PB1; -. DR AlphaFoldDB; Q96E22; -. DR SMR; Q96E22; -. DR BioGRID; 125481; 80. DR ComplexPortal; CPX-6701; Dehydrodolichyl diphosphate synthase complex. DR CORUM; Q96E22; -. DR DIP; DIP-61225N; -. DR FunCoup; Q96E22; 1500. DR IntAct; Q96E22; 47. DR MINT; Q96E22; -. DR STRING; 9606.ENSP00000357480; -. DR GlyCosmos; Q96E22; 2 sites, No reported glycans. DR GlyGen; Q96E22; 2 sites. DR iPTMnet; Q96E22; -. DR PhosphoSitePlus; Q96E22; -. DR BioMuta; NUS1; -. DR DMDM; 74762651; -. DR jPOST; Q96E22; -. DR MassIVE; Q96E22; -. DR PaxDb; 9606-ENSP00000357480; -. DR PeptideAtlas; Q96E22; -. DR ProteomicsDB; 76366; -. DR Pumba; Q96E22; -. DR Antibodypedia; 32563; 111 antibodies from 22 providers. DR DNASU; 116150; -. DR Ensembl; ENST00000368494.4; ENSP00000357480.3; ENSG00000153989.9. DR GeneID; 116150; -. DR KEGG; hsa:116150; -. DR MANE-Select; ENST00000368494.4; ENSP00000357480.3; NM_138459.5; NP_612468.1. DR UCSC; uc003pxw.4; human. DR AGR; HGNC:21042; -. DR ClinPGx; PA162398248; -. DR CTD; 116150; -. DR DisGeNET; 116150; -. DR GeneCards; NUS1; -. DR HGNC; HGNC:21042; NUS1. DR HPA; ENSG00000153989; Low tissue specificity. DR MalaCards; NUS1; -. DR MIM; 610463; gene. DR MIM; 617082; phenotype. DR MIM; 617831; phenotype. DR OpenTargets; ENSG00000153989; -. DR Orphanet; 442835; Non-specific early-onset epileptic encephalopathy. DR VEuPathDB; HostDB:ENSG00000153989; -. DR eggNOG; KOG2818; Eukaryota. DR GeneTree; ENSGT00390000003223; -. DR HOGENOM; CLU_051870_2_1_1; -. DR InParanoid; Q96E22; -. DR OMA; AWSSCAG; -. DR OrthoDB; 19639at2759; -. DR PAN-GO; Q96E22; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q96E22; -. DR BioCyc; MetaCyc:ENSG00000153989-MONOMER; -. DR BRENDA; 2.5.1.87; 2681. DR PathwayCommons; Q96E22; -. DR Reactome; R-HSA-446199; Synthesis of dolichyl-phosphate. DR Reactome; R-HSA-4755609; Defective DHDDS causes RP59. DR SABIO-RK; Q96E22; -. DR SignaLink; Q96E22; -. DR UniPathway; UPA00378; -. DR Agora; ENSG00000153989; -. DR BioGRID-ORCS; 116150; 791 hits in 1115 CRISPR screens. DR ChiTaRS; NUS1; human. DR GenomeRNAi; 116150; -. DR Pharos; Q96E22; Tbio. DR PRO; PR:Q96E22; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; Q96E22; protein. DR Bgee; ENSG00000153989; Expressed in endometrium and 186 other cell types or tissues. DR GO; GO:1904423; C:dehydrodolichyl diphosphate synthase complex; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:MGI. DR GO; GO:0045547; F:ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] activity; IDA:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW. DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW. DR GO; GO:0042632; P:cholesterol homeostasis; IEA:Ensembl. DR GO; GO:0006489; P:dolichyl diphosphate biosynthetic process; IDA:UniProtKB. DR GO; GO:0043048; P:dolichyl monophosphate biosynthetic process; IMP:MGI. DR GO; GO:1903589; P:positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis; IMP:BHF-UCL. DR GO; GO:0090050; P:positive regulation of cell migration involved in sprouting angiogenesis; IMP:BHF-UCL. DR GO; GO:0032383; P:regulation of intracellular cholesterol transport; IGI:MGI. DR GO; GO:0038084; P:vascular endothelial growth factor signaling pathway; IMP:BHF-UCL. DR FunFam; 3.40.1180.10:FF:000008; NUS1, dehydrodolichyl diphosphate synthase subunit; 1. DR Gene3D; 3.40.1180.10; Decaprenyl diphosphate synthase-like; 1. DR InterPro; IPR038887; Nus1/NgBR. DR InterPro; IPR001441; UPP_synth-like. DR InterPro; IPR036424; UPP_synth-like_sf. DR PANTHER; PTHR21528; DEHYDRODOLICHYL DIPHOSPHATE SYNTHASE COMPLEX SUBUNIT NUS1; 1. DR PANTHER; PTHR21528:SF0; DEHYDRODOLICHYL DIPHOSPHATE SYNTHASE COMPLEX SUBUNIT NUS1; 1. DR Pfam; PF01255; Prenyltransf; 1. DR SUPFAM; SSF64005; Undecaprenyl diphosphate synthase; 1. PE 1: Evidence at protein level; KW 3D-structure; Angiogenesis; Congenital disorder of glycosylation; KW Developmental protein; Differentiation; Disease variant; KW Endoplasmic reticulum; Glycoprotein; Intellectual disability; KW Lipid metabolism; Magnesium; Membrane; Metal-binding; KW Proteomics identification; Receptor; Reference proteome; Transferase; KW Transmembrane; Transmembrane helix. FT CHAIN 1..293 FT /note="Dehydrodolichyl diphosphate synthase complex subunit FT NUS1" FT /id="PRO_0000273167" FT TRANSMEM 1..23 FT /note="Helical; Name=1" FT /evidence="ECO:0000303|PubMed:21572394" FT TRANSMEM 35..56 FT /note="Helical; Name=2" FT /evidence="ECO:0000303|PubMed:21572394" FT TRANSMEM 117..135 FT /note="Helical; Name=3" FT /evidence="ECO:0000303|PubMed:21572394" FT MOTIF 290..292 FT /note="RXG motif; crucial for prenyltransferase activity" FT /evidence="ECO:0000269|PubMed:32817466, FT ECO:0000305|PubMed:28842490" FT BINDING 291 FT /ligand="isopentenyl diphosphate" FT /ligand_id="ChEBI:CHEBI:128769" FT /evidence="ECO:0000269|PubMed:32817466" FT BINDING 292 FT /ligand="isopentenyl diphosphate" FT /ligand_id="ChEBI:CHEBI:128769" FT /evidence="ECO:0000269|PubMed:32817466" FT CARBOHYD 144 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:21572394" FT CARBOHYD 271 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:21572394" FT VARIANT 91 FT /note="G -> C (found in a patient with Parkinson's disease; FT likely pathogenic; 40 % reduction in prenyltransferase FT activity)" FT /evidence="ECO:0000269|PubMed:32817466" FT /id="VAR_083900" FT VARIANT 104..293 FT /note="Missing (found in a patient with progressive FT myoclonus epilepsy; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:33798445" FT /id="VAR_085036" FT VARIANT 175 FT /note="N -> Y (in dbSNP:rs28362518)" FT /id="VAR_030092" FT VARIANT 179 FT /note="D -> E (in dbSNP:rs28362519)" FT /id="VAR_030093" FT VARIANT 210 FT /note="Missing (in dbSNP:rs1052237)" FT /id="VAR_030094" FT VARIANT 216 FT /note="K -> R (in dbSNP:rs1052239)" FT /evidence="ECO:0000269|PubMed:9294218" FT /id="VAR_030095" FT VARIANT 219 FT /note="T -> K (in dbSNP:rs1132147)" FT /evidence="ECO:0000269|PubMed:9294218" FT /id="VAR_030096" FT VARIANT 290 FT /note="R -> H (in CDG1AA; loss of function in protein FT glycosylation; 5-fold reduction in catalytic activity and FT reduced affinity for FPP and IPP.; dbSNP:rs886037858)" FT /evidence="ECO:0000269|PubMed:25066056, FT ECO:0000269|PubMed:28842490, ECO:0000269|PubMed:33077723" FT /id="VAR_071210" FT MUTAGEN 100 FT /note="H->A: 3.5-fold reduction in catalytic activity and FT no marked change in affinity for FPP and IPP." FT /evidence="ECO:0000269|PubMed:28842490" FT MUTAGEN 196 FT /note="G->A: Decreases binding to DHDDS." FT /evidence="ECO:0000269|PubMed:32817466" FT MUTAGEN 197 FT /note="K->A: Decreases binding to DHDDS." FT /evidence="ECO:0000269|PubMed:32817466" FT MUTAGEN 200 FT /note="I->A: Disrupts NUS1-DHDDS heterodimerization." FT /evidence="ECO:0000269|PubMed:32817466" FT MUTAGEN 226 FT /note="L->A: Disrupts NUS1-DHDDS heterodimerization." FT /evidence="ECO:0000269|PubMed:32817466" FT MUTAGEN 230 FT /note="L->A: Disrupts NUS1-DHDDS heterodimerization." FT /evidence="ECO:0000269|PubMed:32817466" FT MUTAGEN 252 FT /note="G->A: Disrupts NUS1-DHDDS heterodimerization." FT /evidence="ECO:0000269|PubMed:32817466" FT MUTAGEN 253 FT /note="F->A: Disrupts NUS1-DHDDS heterodimerization." FT /evidence="ECO:0000269|PubMed:32817466" FT MUTAGEN 255 FT /note="P->A: Disrupts NUS1-DHDDS heterodimerization." FT /evidence="ECO:0000269|PubMed:32817466" FT MUTAGEN 292 FT /note="G->A: Almost complete loss of catalytic activity." FT /evidence="ECO:0000269|PubMed:28842490" FT MUTAGEN 293 FT /note="K->KA: Almost complete loss of catalytic activity." FT /evidence="ECO:0000269|PubMed:28842490" FT MUTAGEN 293 FT /note="Missing: Almost complete loss of catalytic FT activity." FT /evidence="ECO:0000269|PubMed:28842490" FT HELIX 79..93 FT /evidence="ECO:0007829|PDB:7PAX" FT STRAND 99..106 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 114..127 FT /evidence="ECO:0007829|PDB:7PAX" FT STRAND 131..136 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 142..144 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 145..157 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 177..187 FT /evidence="ECO:0007829|PDB:7PAX" FT STRAND 188..191 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 193..195 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 197..212 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 218..220 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 223..229 FT /evidence="ECO:0007829|PDB:7PAX" FT TURN 231..234 FT /evidence="ECO:0007829|PDB:7PAX" FT STRAND 239..246 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 256..258 FT /evidence="ECO:0007829|PDB:7PAX" FT STRAND 262..267 FT /evidence="ECO:0007829|PDB:7PAX" FT HELIX 274..286 FT /evidence="ECO:0007829|PDB:7PAX" SQ SEQUENCE 293 AA; 33224 MW; E6A0C9D9B39D4BCA CRC64; MTGLYELVWR VLHALLCLHR TLTSWLRVRF GTWNWIWRRC CRAASAAVLA PLGFTLRKPP AVGRNRRHHR HPRGGSCLAA AHHRMRWRAD GRSLEKLPVH MGLVITEVEQ EPSFSDIASL VVWCMAVGIS YISVYDHQGI FKRNNSRLMD EILKQQQELL GLDCSKYSPE FANSNDKDDQ VLNCHLAVKV LSPEDGKADI VRAAQDFCQL VAQKQKRPTD LDVDTLASLL SSNGCPDPDL VLKFGPVDST LGFLPWHIRL TEIVSLPSHL NISYEDFFSA LRQYAACEQR LGK // ID SYWM_HUMAN Reviewed; 360 AA. AC Q9UGM6; B1ALR1; B2R9D4; Q53FT4; Q5VUD2; Q86TQ0; DT 06-JUN-2002, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 1. DT 28-JAN-2026, entry version 193. DE RecName: Full=Tryptophan--tRNA ligase, mitochondrial; DE EC=6.1.1.2 {ECO:0000269|PubMed:10828066}; DE AltName: Full=(Mt)TrpRS; DE AltName: Full=Tryptophanyl-tRNA synthetase; DE Short=TrpRS; DE Flags: Precursor; GN Name=WARS2; 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), FUNCTION, CATALYTIC ACTIVITY, RP SUBCELLULAR LOCATION, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=10828066; DOI=10.1074/jbc.275.22.16820; RA Jorgensen R., Soegaard T.M.M., Rossing A.B., Martensen P.M., Justesen J.; RT "Identification and characterization of human mitochondrial tryptophanyl- RT tRNA synthetase."; RL J. Biol. Chem. 275:16820-16826(2000). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). 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 MRNA] (ISOFORM 1). RC TISSUE=Kidney proximal tubule; RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., RA Tanaka A., Yokoyama S.; RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT RP SER-50. 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 [7] 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 [8] 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 [9] {ECO:0007744|PDB:5EKD} RP X-RAY CRYSTALLOGRAPHY (1.82 ANGSTROMS) OF 18-360 IN COMPLEX WITH ATP; RP MANGANESE AND SUBSTRATE ANALOG. RA Williams T.L., Carter C.W.; RT "Binding of Mg2+ATP Enhances Inhibition of Human Mitochondrial RT Tryptophanyl-tRNA Synthetase by Indolmycin."; RL Submitted (NOV-2015) to the PDB data bank. RN [10] RP INVOLVEMENT IN NEMMLAS, AND VARIANTS NEMMLAS LEU-100 DEL AND MET-313. RX PubMed=28650581; DOI=10.1002/ajmg.a.38339; RA Theisen B.E., Rumyantseva A., Cohen J.S., Alcaraz W.A., Shinde D.N., RA Tang S., Srivastava S., Pevsner J., Trifunovic A., Fatemi A.; RT "Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, RT causes severe infantile onset leukoencephalopathy."; RL Am. J. Med. Genet. A 173:2505-2510(2017). RN [11] RP VARIANTS PKDYS3 GLY-13 AND TRP-228, AND INVOLVEMENT IN PKDYS3. RX PubMed=29120065; DOI=10.1111/cge.13172; RA Burke E.A., Frucht S.J., Thompson K., Wolfe L.A., Yokoyama T., Bertoni M., RA Huang Y., Sincan M., Adams D.R., Taylor R.W., Gahl W.A., Toro C., RA Malicdan M.C.V.; RT "Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause RT Levodopa-responsive infantile-onset Parkinsonism."; RL Clin. Genet. 93:712-718(2018). RN [12] RP INVOLVEMENT IN NEMMLAS, AND VARIANTS NEMMLAS VAL-45; GLN-77; LEU-178; RP MET-313; LEU-349 AND LYS-352. RX PubMed=28905505; DOI=10.1002/humu.23340; RA Wortmann S.B., Timal S., Venselaar H., Wintjes L.T., Kopajtich R., RA Feichtinger R.G., Onnekink C., Muehlmeister M., Brandt U., Smeitink J.A., RA Veltman J.A., Sperl W., Lefeber D., Pruijn G., Stojanovic V., RA Freisinger P., V Spronsen F., Derks T.G., Veenstra-Knol H.E., Mayr J.A., RA Roetig A., Tarnopolsky M., Prokisch H., Rodenburg R.J.; RT "Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA RT synthase in six individuals with mitochondrial encephalopathy."; RL Hum. Mutat. 38:1786-1795(2017). RN [13] RP VARIANT NEMMLAS GLY-13, CHARACTERIZATION OF VARIANT NEMMLAS GLY-13, RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INVOLVEMENT IN NEMMLAS. RX PubMed=28236339; DOI=10.1002/humu.23205; RA Musante L., Puettmann L., Kahrizi K., Garshasbi M., Hu H., Stehr H., RA Lipkowitz B., Otto S., Jensen L.R., Tzschach A., Jamali P., Wienker T., RA Najmabadi H., Ropers H.H., Kuss A.W.; RT "Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated RT in the aetiology of autosomal recessive intellectual disability."; RL Hum. Mutat. 38:621-636(2017). RN [14] RP VARIANTS NEMMLAS GLY-278 AND MET-313. RX PubMed=30920170; DOI=10.1002/mgg3.654; RA Maffezzini C., Laine I., Dallabona C., Clemente P., Calvo-Garrido J., RA Wibom R., Naess K., Barbaro M., Falk A., Donnini C., Freyer C., RA Wredenberg A., Wedell A.; RT "Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth RT retardation and progressive leukoencephalopathy."; RL Mol. Genet. Genomic Med. 7:e654-e654(2019). RN [15] RP VARIANTS PKDYS3 GLY-13 AND ASP-50, AND INVOLVEMENT IN PKDYS3. RX PubMed=31970218; DOI=10.1002/mdc3.12855; RA Huebers A., Huppertz H.J., Wortmann S.B., Kassubek J.; RT "Mutation of the WARS2 Gene as the Cause of a Severe Hyperkinetic Movement RT Disorder."; RL Mov. Disord. Clin. Pract. 7:88-90(2020). RN [16] RP VARIANTS PKDYS3 GLY-13; ASP-50; LEU-100 DEL AND 208-GLU--LEU-360 DEL. RX PubMed=34890876; DOI=10.1016/j.parkreldis.2021.11.030; RA Skorvanek M., Rektorova I., Mandemakers W., Wagner M., Steinfeld R., RA Orec L., Han V., Pavelekova P., Lackova A., Kulcsarova K., RA Ostrozovicova M., Gdovinova Z., Plecko B., Brunet T., Berutti R., RA Kuipers D.J.S., Boumeester V., Havrankova P., Tijssen M.A.J., RA Kaiyrzhanov R., Rizig M., Houlden H., Winkelmann J., Bonifati V., Zech M., RA Jech R.; RT "WARS2 mutations cause dopa-responsive early-onset parkinsonism and RT progressive myoclonus ataxia."; RL Parkinsonism Relat. Disord. 94:54-61(2022). RN [17] RP VARIANTS NEMMLAS GLY-278 AND MET-313. RX PubMed=35074316; DOI=10.1016/j.parkreldis.2022.01.012; RA Ilinca A., Kafantari E., Puschmann A.; RT "A relatively common hypomorphic variant in WARS2 causes monogenic RT disease."; RL Parkinsonism Relat. Disord. 94:129-131(2022). CC -!- FUNCTION: Catalyzes the attachment of tryptophan to tRNA(Trp) in a two- CC step reaction: tryptophan is first activated by ATP to form Trp-AMP and CC then transferred to the acceptor end of tRNA(Trp). CC {ECO:0000269|PubMed:10828066}. CC -!- CATALYTIC ACTIVITY: CC Reaction=tRNA(Trp) + L-tryptophan + ATP = L-tryptophyl-tRNA(Trp) + AMP CC + diphosphate + H(+); Xref=Rhea:RHEA:24080, Rhea:RHEA-COMP:9671, CC Rhea:RHEA-COMP:9705, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:33019, ChEBI:CHEBI:57912, ChEBI:CHEBI:78442, CC ChEBI:CHEBI:78535, ChEBI:CHEBI:456215; EC=6.1.1.2; CC Evidence={ECO:0000269|PubMed:10828066}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=27 uM for tryptophan {ECO:0000269|PubMed:10828066}; CC KM=401 uM for ATP {ECO:0000269|PubMed:10828066}; CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix CC {ECO:0000269|PubMed:28236339}. Mitochondrion CC {ECO:0000269|PubMed:10828066}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9UGM6-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9UGM6-2; Sequence=VSP_041414, VSP_041415; CC -!- TISSUE SPECIFICITY: Brain. {ECO:0000269|PubMed:28236339}. CC -!- DISEASE: Neurodevelopmental disorder, mitochondrial, with abnormal CC movements and lactic acidosis, with or without seizures (NEMMLAS) CC [MIM:617710]: An autosomal recessive, mitochondrial disorder with a CC broad phenotypic spectrum ranging from severe neonatal lactic acidosis, CC encephalomyopathy and early death to an attenuated course with milder CC manifestations. Clinical features include delayed psychomotor CC development, intellectual disability, hypotonia, dystonia, ataxia, and CC spasticity. Severe combined respiratory chain deficiency may be found CC in severely affected individuals. {ECO:0000269|PubMed:28236339, CC ECO:0000269|PubMed:28650581, ECO:0000269|PubMed:28905505, CC ECO:0000269|PubMed:30920170, ECO:0000269|PubMed:35074316}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Parkinsonism-dystonia 3, childhood-onset (PKDYS3) CC [MIM:619738]: An autosomal recessive neurodegenerative disorder with CC onset in infancy or early childhood. Affected individuals present with CC progressive movement abnormalities, including parkinsonism with tremor, CC dystonia, myoclonus ataxia, and hyperkinetic movements such as CC ballismus. The parkinsonism features may be responsive to treatment CC with levodopa, although many patients develop levodopa-induced CC dyskinesia. Some patients may have mild cognitive impairment or CC psychiatric disturbances. {ECO:0000269|PubMed:29120065, CC ECO:0000269|PubMed:31970218, ECO:0000269|PubMed:34890876}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the class-I aminoacyl-tRNA synthetase 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; AJ242739; CAB63107.1; -; mRNA. DR EMBL; AK223197; BAD96917.1; -; mRNA. DR EMBL; AK313740; BAG36481.1; -; mRNA. DR EMBL; AL359823; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL139420; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL590288; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471122; EAW56693.1; -; Genomic_DNA. DR EMBL; BC044575; AAH44575.1; -; mRNA. DR EMBL; BC039889; -; NOT_ANNOTATED_CDS; mRNA. DR CCDS; CCDS30817.1; -. [Q9UGM6-2] DR CCDS; CCDS900.1; -. [Q9UGM6-1] DR RefSeq; NP_056651.1; NM_015836.4. [Q9UGM6-1] DR RefSeq; NP_957715.1; NM_201263.2. [Q9UGM6-2] DR PDB; 5EKD; X-ray; 1.82 A; A/B=18-360. DR PDBsum; 5EKD; -. DR AlphaFoldDB; Q9UGM6; -. DR SMR; Q9UGM6; -. DR BioGRID; 115633; 46. DR FunCoup; Q9UGM6; 1490. DR IntAct; Q9UGM6; 7. DR STRING; 9606.ENSP00000235521; -. DR DrugBank; DB00150; Tryptophan. DR GlyGen; Q9UGM6; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q9UGM6; -. DR PhosphoSitePlus; Q9UGM6; -. DR BioMuta; WARS2; -. DR DMDM; 21362967; -. DR jPOST; Q9UGM6; -. DR MassIVE; Q9UGM6; -. DR PaxDb; 9606-ENSP00000235521; -. DR PeptideAtlas; Q9UGM6; -. DR ProteomicsDB; 84244; -. [Q9UGM6-1] DR ProteomicsDB; 84245; -. [Q9UGM6-2] DR Pumba; Q9UGM6; -. DR Antibodypedia; 33903; 78 antibodies from 27 providers. DR DNASU; 10352; -. DR Ensembl; ENST00000235521.5; ENSP00000235521.4; ENSG00000116874.13. [Q9UGM6-1] DR Ensembl; ENST00000369426.9; ENSP00000358434.5; ENSG00000116874.13. [Q9UGM6-2] DR GeneID; 10352; -. DR KEGG; hsa:10352; -. DR MANE-Select; ENST00000235521.5; ENSP00000235521.4; NM_015836.4; NP_056651.1. DR UCSC; uc001ehm.4; human. [Q9UGM6-1] DR AGR; HGNC:12730; -. DR ClinPGx; PA37341; -. DR CTD; 10352; -. DR DisGeNET; 10352; -. DR GeneCards; WARS2; -. DR GeneReviews; WARS2; -. DR HGNC; HGNC:12730; WARS2. DR HPA; ENSG00000116874; Low tissue specificity. DR MalaCards; WARS2; -. DR MIM; 604733; gene. DR MIM; 617710; phenotype. DR MIM; 619738; phenotype. DR OpenTargets; ENSG00000116874; -. DR Orphanet; 238455; Infantile dystonia-parkinsonism. DR Orphanet; 572798; WARS2-related combined oxidative phosphorylation defect. DR VEuPathDB; HostDB:ENSG00000116874; -. DR eggNOG; KOG2713; Eukaryota. DR GeneTree; ENSGT00940000153724; -. DR HOGENOM; CLU_029244_3_0_1; -. DR InParanoid; Q9UGM6; -. DR OMA; GWGQFKP; -. DR OrthoDB; 15808at2759; -. DR PAN-GO; Q9UGM6; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q9UGM6; -. DR BRENDA; 6.1.1.2; 2681. DR PathwayCommons; Q9UGM6; -. DR Reactome; R-HSA-379726; Mitochondrial tRNA aminoacylation. DR SignaLink; Q9UGM6; -. DR SIGNOR; Q9UGM6; -. DR Agora; ENSG00000116874; -. DR BioGRID-ORCS; 10352; 258 hits in 1189 CRISPR screens. DR ChiTaRS; WARS2; human. DR GeneWiki; WARS2; -. DR GenomeRNAi; 10352; -. DR Pharos; Q9UGM6; Tbio. DR PRO; PR:Q9UGM6; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q9UGM6; protein. DR Bgee; ENSG00000116874; Expressed in primordial germ cell in gonad and 144 other cell types or tissues. DR GO; GO:0005759; C:mitochondrial matrix; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0004830; F:tryptophan-tRNA ligase activity; IDA:UniProtKB. DR GO; GO:0070183; P:mitochondrial tryptophanyl-tRNA aminoacylation; IBA:GO_Central. DR GO; GO:0045766; P:positive regulation of angiogenesis; IEA:Ensembl. DR GO; GO:0006418; P:tRNA aminoacylation for protein translation; TAS:Reactome. DR GO; GO:0001570; P:vasculogenesis; IEA:Ensembl. DR CDD; cd00806; TrpRS_core; 1. DR FunFam; 3.40.50.620:FF:000082; MSW1p Mitochondrial tryptophanyl-tRNA synthetase; 1. DR FunFam; 1.10.240.10:FF:000002; Tryptophan--tRNA ligase; 1. DR Gene3D; 3.40.50.620; HUPs; 1. DR Gene3D; 1.10.240.10; Tyrosyl-Transfer RNA Synthetase; 1. DR HAMAP; MF_00140_B; Trp_tRNA_synth_B; 1. DR InterPro; IPR001412; aa-tRNA-synth_I_CS. DR InterPro; IPR002305; aa-tRNA-synth_Ic. DR InterPro; IPR014729; Rossmann-like_a/b/a_fold. DR InterPro; IPR002306; Trp-tRNA-ligase. DR InterPro; IPR024109; Trp-tRNA-ligase_bac-type. DR InterPro; IPR050203; Trp-tRNA_synthetase. DR NCBIfam; TIGR00233; trpS; 1. DR PANTHER; PTHR43766; TRYPTOPHAN--TRNA LIGASE, MITOCHONDRIAL; 1. DR PANTHER; PTHR43766:SF1; TRYPTOPHAN--TRNA LIGASE, MITOCHONDRIAL; 1. DR Pfam; PF00579; tRNA-synt_1b; 1. DR PRINTS; PR01039; TRNASYNTHTRP. DR SUPFAM; SSF52374; Nucleotidylyl transferase; 1. DR PROSITE; PS00178; AA_TRNA_LIGASE_I; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Aminoacyl-tRNA synthetase; ATP-binding; KW Disease variant; Dystonia; Ligase; Mitochondrion; Nucleotide-binding; KW Parkinsonism; Primary mitochondrial disease; Protein biosynthesis; KW Proteomics identification; Reference proteome; Transit peptide. FT TRANSIT 1..18 FT /note="Mitochondrion" FT CHAIN 19..360 FT /note="Tryptophan--tRNA ligase, mitochondrial" FT /id="PRO_0000035828" FT BINDING 42 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0007744|PDB:5EKD" FT BINDING 48..51 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0007744|PDB:5EKD" FT BINDING 167 FT /ligand="L-tryptophan" FT /ligand_id="ChEBI:CHEBI:57912" FT /evidence="ECO:0007744|PDB:5EKD" FT BINDING 179..181 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0007744|PDB:5EKD" FT BINDING 217 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0007744|PDB:5EKD" FT BINDING 226..230 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0007744|PDB:5EKD" FT VAR_SEQ 212..220 FT /note="TSMKKVKSL -> SMCVLVFLT (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_041414" FT VAR_SEQ 221..360 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_041415" FT VARIANT 13 FT /note="W -> G (in NEMMLAS and PKDYS3; hypomorphic variant, FT clinically relevant when present in trans with an amorphic FT variant; impaired mitochondrial localization; FT dbSNP:rs139548132)" FT /evidence="ECO:0000269|PubMed:28236339, FT ECO:0000269|PubMed:29120065, ECO:0000269|PubMed:31970218, FT ECO:0000269|PubMed:34890876" FT /id="VAR_078435" FT VARIANT 45 FT /note="G -> V (in NEMMLAS; dbSNP:rs1553241795)" FT /evidence="ECO:0000269|PubMed:28905505" FT /id="VAR_079734" FT VARIANT 50 FT /note="G -> D (in PKDYS3; dbSNP:rs1571323203)" FT /evidence="ECO:0000269|PubMed:31970218, FT ECO:0000269|PubMed:34890876" FT /id="VAR_086908" FT VARIANT 50 FT /note="G -> S (in dbSNP:rs11552864)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_028848" FT VARIANT 77 FT /note="H -> Q (in NEMMLAS; uncertain significance; FT dbSNP:rs766501807)" FT /evidence="ECO:0000269|PubMed:28905505" FT /id="VAR_079735" FT VARIANT 100 FT /note="Missing (in NEMMLAS and PKDYS3; dbSNP:rs772867219)" FT /evidence="ECO:0000269|PubMed:28650581, FT ECO:0000269|PubMed:34890876" FT /id="VAR_079736" FT VARIANT 178 FT /note="V -> L (in NEMMLAS; dbSNP:rs912133959)" FT /evidence="ECO:0000269|PubMed:28905505" FT /id="VAR_079737" FT VARIANT 208..360 FT /note="Missing (in PKDYS3)" FT /evidence="ECO:0000269|PubMed:34890876" FT /id="VAR_086909" FT VARIANT 228 FT /note="S -> W (in PKDYS3; dbSNP:rs1647600390)" FT /evidence="ECO:0000269|PubMed:29120065" FT /id="VAR_086910" FT VARIANT 267 FT /note="A -> P (in dbSNP:rs3790549)" FT /id="VAR_020217" FT VARIANT 278 FT /note="V -> G (in NEMMLAS; dbSNP:rs765904496)" FT /evidence="ECO:0000269|PubMed:30920170, FT ECO:0000269|PubMed:35074316" FT /id="VAR_086911" FT VARIANT 313 FT /note="K -> M (in NEMMLAS; dbSNP:rs145867327)" FT /evidence="ECO:0000269|PubMed:28650581, FT ECO:0000269|PubMed:28905505, ECO:0000269|PubMed:30920170, FT ECO:0000269|PubMed:35074316" FT /id="VAR_079738" FT VARIANT 349 FT /note="V -> L (in NEMMLAS; dbSNP:rs1170780314)" FT /evidence="ECO:0000269|PubMed:28905505" FT /id="VAR_079739" FT VARIANT 352 FT /note="E -> K (in NEMMLAS; uncertain significance; FT dbSNP:rs563341344)" FT /evidence="ECO:0000269|PubMed:28905505" FT /id="VAR_079740" FT VARIANT 360 FT /note="L -> P (in dbSNP:rs17023101)" FT /id="VAR_052407" FT CONFLICT 151 FT /note="H -> R (in Ref. 3; BAD96917)" FT /evidence="ECO:0000305" FT STRAND 37..41 FT /evidence="ECO:0007829|PDB:5EKD" FT STRAND 43..45 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 49..54 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 56..65 FT /evidence="ECO:0007829|PDB:5EKD" FT STRAND 69..73 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 75..78 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 85..102 FT /evidence="ECO:0007829|PDB:5EKD" FT TURN 106..108 FT /evidence="ECO:0007829|PDB:5EKD" FT STRAND 109..113 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 114..116 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 119..128 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 133..137 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 140..143 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 147..152 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 155..169 FT /evidence="ECO:0007829|PDB:5EKD" FT TURN 170..172 FT /evidence="ECO:0007829|PDB:5EKD" FT STRAND 175..177 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 180..182 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 183..200 FT /evidence="ECO:0007829|PDB:5EKD" FT STRAND 208..210 FT /evidence="ECO:0007829|PDB:5EKD" FT TURN 213..216 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 234..236 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 244..253 FT /evidence="ECO:0007829|PDB:5EKD" FT TURN 266..268 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 270..283 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 287..293 FT /evidence="ECO:0007829|PDB:5EKD" FT TURN 294..296 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 299..324 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 328..357 FT /evidence="ECO:0007829|PDB:5EKD" SQ SEQUENCE 360 AA; 40147 MW; 8C80DF6FCA214A91 CRC64; MALHSMRKAR ERWSFIRALH KGSAAAPALQ KDSKKRVFSG IQPTGILHLG NYLGAIESWV RLQDEYDSVL YSIVDLHSIT VPQDPAVLRQ SILDMTAVLL ACGINPEKSI LFQQSQVSEH TQLSWILSCM VRLPRLQHLH QWKAKTTKQK HDGTVGLLTY PVLQAADILL YKSTHVPVGE DQVQHMELVQ DLAQGFNKKY GEFFPVPESI LTSMKKVKSL RDPSAKMSKS DPDKLATVRI TDSPEEIVQK FRKAVTDFTS EVTYDPAGRA GVSNIVAVHA AVTGLSVEEV VRRSAGMNTA RYKLAVADAV IEKFAPIKRE IEKLKLDKDH LEKVLQIGSA KAKELAYTVC QEVKKLVGFL //