ID PRKRA_HUMAN Reviewed; 313 AA. AC O75569; A8K3I6; Q53G24; Q6X7T5; Q8NDK4; DT 21-FEB-2006, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1998, sequence version 1. DT 28-JAN-2026, entry version 212. DE RecName: Full=Interferon-inducible double-stranded RNA-dependent protein kinase activator A; DE AltName: Full=PKR-associated protein X; DE AltName: Full=PKR-associating protein X; DE AltName: Full=Protein activator of the interferon-induced protein kinase; DE AltName: Full=Protein kinase, interferon-inducible double-stranded RNA-dependent activator; GN Name=PRKRA {ECO:0000312|HGNC:HGNC:9438}; Synonyms=PACT, RAX; GN ORFNames=HSD-14, HSD14; 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, AND INTERACTION WITH RP EIF2AK2. RC TISSUE=Placenta; RX PubMed=9687506; DOI=10.1093/emboj/17.15.4379; RA Patel R.C., Sen G.C.; RT "PACT, a protein activator of the interferon-induced protein kinase, PKR."; RL EMBO J. 17:4379-4390(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION. RX PubMed=10336432; DOI=10.1074/jbc.274.22.15427; RA Ito T., Yang M., May W.S.; RT "RAX, a cellular activator for double-stranded RNA-dependent protein kinase RT during stress signaling."; RL J. Biol. Chem. 274:15427-15432(1999). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Testis; RA Hu T.H., Miao S.Y., Zhang X.D., Qiao Y., Liang G., Wang L.F.; RT "A new spermatogenesis-related gene."; RL Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Brain; RX PubMed=11230166; DOI=10.1101/gr.gr1547r; RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S., RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J., RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W., RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B., RA Klein M., Poustka A.; RT "Towards a catalog of human genes and proteins: sequencing and analysis of RT 500 novel complete protein coding human cDNAs."; RL Genome Res. 11:422-435(2001). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Heart; 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 [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). 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 [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [10] 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 [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). 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 [12] RP FUNCTION, AND INTERACTION WITH EIF2AK2. RX PubMed=11238927; DOI=10.1128/mcb.21.6.1908-1920.2001; RA Peters G.A., Hartmann R., Qin J., Sen G.C.; RT "Modular structure of PACT: distinct domains for binding and activating RT PKR."; RL Mol. Cell. Biol. 21:1908-1920(2001). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [14] RP FUNCTION, INTERACTION WITH DICER1; AGO2 AND TARBP2, SUBCELLULAR LOCATION, RP AND MUTAGENESIS OF 298-ALA-ALA-299. RX PubMed=16424907; DOI=10.1038/sj.emboj.7600942; RA Lee Y., Hur I., Park S.-Y., Kim Y.-K., Suh M.R., Kim V.N.; RT "The role of PACT in the RNA silencing pathway."; RL EMBO J. 25:522-532(2006). RN [15] RP FUNCTION, INTERACTION WITH EIF2AK2, SUBCELLULAR LOCATION, PHOSPHORYLATION RP AT SER-246 AND SER-287, AND MUTAGENESIS OF SER-18; GLN-243; SER-246; RP ASP-260; ASP-262; SER-265; GLN-271; SER-279; SER-287; GLY-288 AND CYS-291. RX PubMed=16982605; DOI=10.1074/jbc.m607714200; RA Peters G.A., Li S., Sen G.C.; RT "Phosphorylation of specific serine residues in the PKR activation domain RT of PACT is essential for its ability to mediate apoptosis."; RL J. Biol. Chem. 281:35129-35136(2006). RN [16] RP FUNCTION, SELF-ASSOCIATION, INTERACTION WITH DICER1 AND TARBP2, AND RP SUBCELLULAR LOCATION. RX PubMed=17452327; DOI=10.1074/jbc.m611768200; RA Kok K.H., Ng M.-H., Ching Y.-P., Jin D.-Y.; RT "Human TRBP and PACT directly interact with each other and associate with RT dicer to facilitate the production of small interfering RNA."; RL J. Biol. Chem. 282:17649-17657(2007). RN [17] RP INTERACTION WITH DUS2L. RX PubMed=18096616; DOI=10.1093/nar/gkm1129; RA Mittelstadt M., Frump A., Khuu T., Fowlkes V., Handy I., Patel C.V., RA Patel R.C.; RT "Interaction of human tRNA-dihydrouridine synthase-2 with interferon- RT induced protein kinase PKR."; RL Nucleic Acids Res. 36:998-1008(2008). RN [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-18, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [19] RP SELF-ASSOCIATION, INTERACTION WITH EIF2AK2 AND TARBP2, AND SUBCELLULAR RP LOCATION. RX PubMed=18421256; DOI=10.4161/rna.5.2.6069; RA Laraki G., Clerzius G., Daher A., Melendez-Pena C., Daniels S., RA Gatignol A.; RT "Interactions between the double-stranded RNA-binding proteins TRBP and RT PACT define the Medipal domain that mediates protein-protein RT interactions."; RL RNA Biol. 5:92-103(2008). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-18, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [21] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [22] RP INTERACTION WITH EBOLAVIRUS VP35 (MICROBIAL INFECTION). RX PubMed=21228243; DOI=10.1128/jvi.01160-10; RA Fabozzi G., Nabel C.S., Dolan M.A., Sullivan N.J.; RT "Ebolavirus proteins suppress the effects of small interfering RNA by RT direct interaction with the mammalian RNA interference pathway."; RL J. Virol. 85:2512-2523(2011). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-18, AND IDENTIFICATION BY RP 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 [24] RP SUBCELLULAR LOCATION. RX PubMed=22214662; DOI=10.4161/cc.11.2.18999; RA Bennett R.L., Pan Y., Christian J., Hui T., May W.S. Jr.; RT "The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and RT activation, leading to G(1) arrest."; RL Cell Cycle 11:407-417(2012). RN [25] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-18 AND SER-167, AND RP IDENTIFICATION 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 [26] RP INTERACTION WITH EBOLAVIRUS PROTEIN VP35 (MICROBIAL INFECTION) AND RIGI. RX PubMed=23870315; DOI=10.1016/j.chom.2013.06.010; RA Luthra P., Ramanan P., Mire C.E., Weisend C., Tsuda Y., Yen B., Liu G., RA Leung D.W., Geisbert T.W., Ebihara H., Amarasinghe G.K., Basler C.F.; RT "Mutual antagonism between the Ebola virus VP35 protein and the RIG-I RT activator PACT determines infection outcome."; RL Cell Host Microbe 14:74-84(2013). RN [27] 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 [28] RP INTERACTION WITH HUMAN HERPES VIRUS 8 PROTEIN KTA/ORF57 (MICROBIAL RP INFECTION). RX PubMed=29084250; DOI=10.1371/journal.ppat.1006677; RA Sharma N.R., Majerciak V., Kruhlak M.J., Zheng Z.M.; RT "KSHV inhibits stress granule formation by viral ORF57 blocking PKR RT activation."; RL PLoS Pathog. 13:e1006677-e1006677(2017). RN [29] RP STRUCTURE BY NMR OF 32-104. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the DSRM domain of protein activator of the RT interferon-induced protein kinase."; RL Submitted (SEP-2006) to the PDB data bank. RN [30] RP VARIANT DYT16 LEU-222. RX PubMed=18243799; DOI=10.1016/s1474-4422(08)70022-x; RA Camargos S., Scholz S., Simon-Sanchez J., Paisan-Ruiz C., Lewis P., RA Hernandez D., Ding J., Gibbs J.R., Cookson M.R., Bras J., Guerreiro R., RA Oliveira C.R., Lees A., Hardy J., Cardoso F., Singleton A.B.; RT "DYT16, a novel young-onset dystonia-parkinsonism disorder: identification RT of a segregating mutation in the stress-response protein PRKRA."; RL Lancet Neurol. 7:207-215(2008). RN [31] RP INVOLVEMENT IN DYT16. RX PubMed=18420150; DOI=10.1016/s1474-4422(08)70075-9; RA Seibler P., Djarmati A., Langpap B., Hagenah J., Schmidt A., RA Brueggemann N., Siebner H., Jabusch H.-C., Altenmueller E., Muenchau A., RA Lohmann K., Klein C.; RT "A heterozygous frameshift mutation in PRKRA (DYT16) associated with RT generalised dystonia in a German patient."; RL Lancet Neurol. 7:380-381(2008). CC -!- FUNCTION: Activates EIF2AK2/PKR in the absence of double-stranded RNA CC (dsRNA), leading to phosphorylation of EIF2S1/EFI2-alpha and inhibition CC of translation and induction of apoptosis. Required for siRNA CC production by DICER1 and for subsequent siRNA-mediated post- CC transcriptional gene silencing. Does not seem to be required for CC processing of pre-miRNA to miRNA by DICER1. Promotes UBC9-p53/TP53 CC association and sumoylation and phosphorylation of p53/TP53 at 'Lys- CC 386' at 'Ser-392' respectively and enhances its activity in a CC EIF2AK2/PKR-dependent manner (By similarity). May function as regulator CC of gastric epithelial differentiation (By similarity). {ECO:0000250, CC ECO:0000250|UniProtKB:Q9WTX2, ECO:0000269|PubMed:10336432, CC ECO:0000269|PubMed:11238927, ECO:0000269|PubMed:16424907, CC ECO:0000269|PubMed:16982605, ECO:0000269|PubMed:17452327, CC ECO:0000269|PubMed:9687506}. CC -!- SUBUNIT: Homodimer. Interacts with EIF2AK2/PKR through its DRBM CC domains. Interacts with DICER1, AGO2 and TARBP2. Also able to interact CC with dsRNA. Interacts with UBC9 (By similarity). Forms a complex with CC UBC9 and p53/TP53 (By similarity). Interacts with DUS2L (via DRBM CC domain). Interacts with RIGI. {ECO:0000250, CC ECO:0000269|PubMed:11238927, ECO:0000269|PubMed:16424907, CC ECO:0000269|PubMed:16982605, ECO:0000269|PubMed:17452327, CC ECO:0000269|PubMed:18096616, ECO:0000269|PubMed:18421256, CC ECO:0000269|PubMed:23870315, ECO:0000269|PubMed:9687506}. CC -!- SUBUNIT: (Microbial infection) Interacts with ebolavirus protein VP35; CC this interaction inhibits the interaction between RIGI and PRKRA. In CC addition, this interaction disrupts the interaction between VP35 and CC the viral polymerase L. So the VP35-PRKRA interaction plays a critical CC role in determining the outcome of ebolavirus infection CC (PubMed:23870315). The interaction PRKRA-VP35 also prevents PRKRA CC binding to DICER1 and thus allows the virus to counteract host RNA CC silencing (PubMed:21228243). {ECO:0000269|PubMed:21228243, CC ECO:0000269|PubMed:23870315}. CC -!- SUBUNIT: (Microbial infection) Interacts with human herpesvirus 8 CC protein MTA/ORF57; this interaction inhibits stress granule formation. CC {ECO:0000269|PubMed:29084250}. CC -!- INTERACTION: CC O75569; P78563-4: ADARB1; NbExp=3; IntAct=EBI-713955, EBI-12002366; CC O75569; Q9UKV8: AGO2; NbExp=5; IntAct=EBI-713955, EBI-528269; CC O75569; Q03701: CEBPZ; NbExp=3; IntAct=EBI-713955, EBI-1046778; CC O75569; Q9UPY3: DICER1; NbExp=9; IntAct=EBI-713955, EBI-395506; CC O75569; Q08426: EHHADH; NbExp=3; IntAct=EBI-713955, EBI-2339219; CC O75569; P19525: EIF2AK2; NbExp=6; IntAct=EBI-713955, EBI-640775; CC O75569; Q9BYX4: IFIH1; NbExp=4; IntAct=EBI-713955, EBI-6115771; CC O75569; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-713955, EBI-739832; CC O75569; Q9NX58: LYAR; NbExp=7; IntAct=EBI-713955, EBI-713507; CC O75569; O15226: NKRF; NbExp=6; IntAct=EBI-713955, EBI-766011; CC O75569; O75928-2: PIAS2; NbExp=3; IntAct=EBI-713955, EBI-348567; CC O75569; O75569: PRKRA; NbExp=6; IntAct=EBI-713955, EBI-713955; CC O75569; O95786: RIGI; NbExp=5; IntAct=EBI-713955, EBI-995350; CC O75569; Q9Y3U8: RPL36; NbExp=3; IntAct=EBI-713955, EBI-1057689; CC O75569; O95793: STAU1; NbExp=5; IntAct=EBI-713955, EBI-358174; CC O75569; Q96SI9: STRBP; NbExp=4; IntAct=EBI-713955, EBI-740355; CC O75569; Q15633: TARBP2; NbExp=15; IntAct=EBI-713955, EBI-978581; CC O75569; Q9HA38: ZMAT3; NbExp=3; IntAct=EBI-713955, EBI-2548480; CC O75569; Q9H898-2: ZMAT4; NbExp=4; IntAct=EBI-713955, EBI-11529334; CC O75569; P38732: EFM1; Xeno; NbExp=4; IntAct=EBI-713955, EBI-24379; CC O75569; P03416: N; Xeno; NbExp=6; IntAct=EBI-713955, EBI-25639341; CC O75569; P0DTC9: N; Xeno; NbExp=8; IntAct=EBI-713955, EBI-25475856; CC O75569; P59595: N; Xeno; NbExp=6; IntAct=EBI-713955, EBI-7602718; CC O75569; P03496: NS; Xeno; NbExp=3; IntAct=EBI-713955, EBI-2547442; CC O75569; Q67020: PA; Xeno; NbExp=3; IntAct=EBI-713955, EBI-11514477; CC O75569; Q05127: VP35; Xeno; NbExp=2; IntAct=EBI-713955, EBI-6148294; CC O75569-1; P19525: EIF2AK2; NbExp=3; IntAct=EBI-15588172, EBI-640775; CC -!- SUBCELLULAR LOCATION: Cytoplasm, perinuclear region. Cytoplasm. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=O75569-1; Sequence=Displayed; CC Name=2; CC IsoId=O75569-2; Sequence=VSP_017283; CC Name=3; CC IsoId=O75569-3; Sequence=VSP_017282; CC -!- DOMAIN: Self-association may occur via interactions between DRBM CC domains as follows: DRBM 1/DRBM 1, DRBM 1/DRBM 2, DRBM 2/DRBM 2 or DRBM CC 3/DRBM3. CC -!- PTM: Phosphorylated at Ser-246 in unstressed cells and at Ser-287 in CC stressed cells. Phosphorylation at Ser-246 appears to be a prerequisite CC for subsequent phosphorylation at Ser-287. Phosphorylation at Ser-246 CC and Ser-287 are necessary for activation of EIF2AK2/PKR under CC conditions of stress. {ECO:0000269|PubMed:16982605}. CC -!- DISEASE: Dystonia 16 (DYT16) [MIM:612067]: An early-onset dystonia- CC parkinsonism disorder. Dystonia is defined by the presence of sustained CC involuntary muscle contraction, often leading to abnormal postures. CC DYT16 patients have progressive, generalized dystonia with axial muscle CC involvement, oro-mandibular (sardonic smile) and laryngeal dystonia CC and, in some cases, parkinsonian features. CC {ECO:0000269|PubMed:18243799, ECO:0000269|PubMed:18420150}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the PRKRA 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; AF072860; AAC25672.1; -; mRNA. DR EMBL; AF083033; AAD33099.1; -; mRNA. DR EMBL; AY251164; AAP20061.1; -; mRNA. DR EMBL; AL136615; CAB66550.1; -; mRNA. DR EMBL; AL833867; CAD38725.1; -; Transcribed_RNA. DR EMBL; BT007243; AAP35907.1; -; mRNA. DR EMBL; AK290601; BAF83290.1; -; mRNA. DR EMBL; CR533525; CAG38556.1; -; mRNA. DR EMBL; AK223107; BAD96827.1; -; mRNA. DR EMBL; AC009948; AAX88882.1; -; Genomic_DNA. DR EMBL; CH471058; EAX11036.1; -; Genomic_DNA. DR EMBL; BC009470; AAH09470.1; -; mRNA. DR CCDS; CCDS2279.1; -. [O75569-1] DR CCDS; CCDS46460.1; -. [O75569-2] DR CCDS; CCDS46461.1; -. [O75569-3] DR RefSeq; NP_001132989.1; NM_001139517.1. [O75569-2] DR RefSeq; NP_001132990.1; NM_001139518.1. [O75569-3] DR RefSeq; NP_003681.1; NM_003690.5. [O75569-1] DR PDB; 2DIX; NMR; -; A=33-103. DR PDB; 8ZU6; NMR; -; A/B=240-309. DR PDBsum; 2DIX; -. DR PDBsum; 8ZU6; -. DR AlphaFoldDB; O75569; -. DR EMDB; EMD-5604; -. DR EMDB; EMD-5605; -. DR EMDB; EMD-5606; -. DR SMR; O75569; -. DR BioGRID; 114143; 434. DR ComplexPortal; CPX-1072; RISC-loading complex, PRKRA variant. DR DIP; DIP-41809N; -. DR FunCoup; O75569; 1598. DR IntAct; O75569; 353. DR MINT; O75569; -. DR STRING; 9606.ENSP00000318176; -. DR GlyGen; O75569; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; O75569; -. DR PhosphoSitePlus; O75569; -. DR SwissPalm; O75569; -. DR BioMuta; PRKRA; -. DR CPTAC; CPTAC-994; -. DR jPOST; O75569; -. DR MassIVE; O75569; -. DR PaxDb; 9606-ENSP00000318176; -. DR PeptideAtlas; O75569; -. DR ProteomicsDB; 50088; -. [O75569-1] DR ProteomicsDB; 50089; -. [O75569-2] DR ProteomicsDB; 50090; -. [O75569-3] DR Pumba; O75569; -. DR Antibodypedia; 3306; 380 antibodies from 38 providers. DR DNASU; 8575; -. DR Ensembl; ENST00000325748.9; ENSP00000318176.4; ENSG00000180228.15. [O75569-1] DR Ensembl; ENST00000432031.6; ENSP00000393883.2; ENSG00000180228.15. [O75569-2] DR Ensembl; ENST00000487082.5; ENSP00000430604.1; ENSG00000180228.15. [O75569-3] DR GeneID; 8575; -. DR KEGG; hsa:8575; -. DR MANE-Select; ENST00000325748.9; ENSP00000318176.4; NM_003690.5; NP_003681.1. DR UCSC; uc002umd.4; human. [O75569-1] DR AGR; HGNC:9438; -. DR ClinPGx; PA33780; -. DR CTD; 8575; -. DR DisGeNET; 8575; -. DR GeneCards; PRKRA; -. DR HGNC; HGNC:9438; PRKRA. DR HPA; ENSG00000180228; Low tissue specificity. DR MalaCards; PRKRA; -. DR MIM; 603424; gene. DR MIM; 612067; phenotype. DR OpenTargets; ENSG00000180228; -. DR Orphanet; 210571; Dystonia 16. DR VEuPathDB; HostDB:ENSG00000180228; -. DR eggNOG; KOG3732; Eukaryota. DR GeneTree; ENSGT00940000157618; -. DR HOGENOM; CLU_048292_0_0_1; -. DR InParanoid; O75569; -. DR OMA; PEYEFEK; -. DR OrthoDB; 10056847at2759; -. DR PAN-GO; O75569; 8 GO annotations based on evolutionary models. DR PhylomeDB; O75569; -. DR PathwayCommons; O75569; -. DR Reactome; R-HSA-203927; MicroRNA (miRNA) biogenesis. DR Reactome; R-HSA-426486; Small interfering RNA (siRNA) biogenesis. DR Reactome; R-HSA-9833482; PKR-mediated signaling. DR SignaLink; O75569; -. DR SIGNOR; O75569; -. DR Agora; ENSG00000180228; -. DR BioGRID-ORCS; 8575; 382 hits in 1167 CRISPR screens. DR ChiTaRS; PRKRA; human. DR EvolutionaryTrace; O75569; -. DR GeneWiki; PRKRA; -. DR GenomeRNAi; 8575; -. DR Pharos; O75569; Tbio. DR PRO; PR:O75569; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; O75569; protein. DR Bgee; ENSG00000180228; Expressed in sperm and 210 other cell types or tissues. DR ExpressionAtlas; O75569; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0016442; C:RISC complex; IBA:GO_Central. DR GO; GO:0070578; C:RISC-loading complex; IDA:BHF-UCL. DR GO; GO:0003725; F:double-stranded RNA binding; IDA:BHF-UCL. DR GO; GO:0008047; F:enzyme activator activity; IDA:UniProt. DR GO; GO:0019899; F:enzyme binding; IPI:BHF-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0070883; F:pre-miRNA binding; IDA:BHF-UCL. DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0035197; F:siRNA binding; IBA:GO_Central. DR GO; GO:0140374; P:antiviral innate immune response; IDA:UniProt. DR GO; GO:0034599; P:cellular response to oxidative stress; IEA:Ensembl. DR GO; GO:0006955; P:immune response; TAS:ProtInc. DR GO; GO:0042474; P:middle ear morphogenesis; IEA:Ensembl. DR GO; GO:0035196; P:miRNA processing; IDA:BHF-UCL. DR GO; GO:0008285; P:negative regulation of cell population proliferation; TAS:ProtInc. DR GO; GO:0042473; P:outer ear morphogenesis; IEA:Ensembl. DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0031054; P:pre-miRNA processing; IDA:BHF-UCL. DR GO; GO:0050821; P:protein stabilization; IMP:BHF-UCL. DR GO; GO:0070920; P:regulation of regulatory ncRNA processing; IBA:GO_Central. DR GO; GO:0009615; P:response to virus; TAS:ProtInc. DR GO; GO:0070922; P:RISC complex assembly; IDA:ComplexPortal. DR GO; GO:0030422; P:siRNA processing; IDA:UniProtKB. DR GO; GO:0048705; P:skeletal system morphogenesis; IEA:Ensembl. DR CDD; cd19889; DSRM_PRKRA_rpt1; 1. DR CDD; cd19891; DSRM_PRKRA_rpt2; 1. DR CDD; cd19892; DSRM_PRKRA_rpt3; 1. DR FunFam; 3.30.160.20:FF:000005; Putative double-stranded RNA-specific adenosine deaminase; 1. DR FunFam; 3.30.160.20:FF:000019; RISC-loading complex subunit TARBP2; 1. DR FunFam; 3.30.160.20:FF:000018; RISC-loading complex subunit TARBP2 isoform X3; 1. DR Gene3D; 3.30.160.20; -; 3. DR InterPro; IPR014720; dsRBD_dom. DR InterPro; IPR044465; PRKRA_DSRM_1. DR InterPro; IPR044466; PRKRA_DSRM_2. DR InterPro; IPR044467; PRKRA_DSRM_3. DR InterPro; IPR051247; RLC_Component. DR PANTHER; PTHR46205:SF2; INTERFERON-INDUCIBLE DOUBLE-STRANDED RNA-DEPENDENT PROTEIN KINASE ACTIVATOR A; 1. DR PANTHER; PTHR46205; LOQUACIOUS, ISOFORM B; 1. DR Pfam; PF00035; dsrm; 2. DR SMART; SM00358; DSRM; 3. DR SUPFAM; SSF54768; dsRNA-binding domain-like; 3. DR PROSITE; PS50137; DS_RBD; 3. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Disease variant; Dystonia; KW Host-virus interaction; Parkinsonism; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; RNA-binding; KW RNA-mediated gene silencing. FT CHAIN 1..313 FT /note="Interferon-inducible double-stranded RNA-dependent FT protein kinase activator A" FT /id="PRO_0000223609" FT DOMAIN 34..101 FT /note="DRBM 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00266" FT DOMAIN 126..194 FT /note="DRBM 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00266" FT DOMAIN 240..308 FT /note="DRBM 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00266" FT REGION 1..103 FT /note="Sufficient for self-association and interaction with FT TARBP2" FT REGION 1..21 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 102..195 FT /note="Sufficient for self-association and interaction with FT TARBP2" FT REGION 195..313 FT /note="Sufficient for self-association and interaction with FT TARBP2" FT COMPBIAS 1..18 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 18 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 167 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 246 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:16982605" FT MOD_RES 287 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:16982605" FT VAR_SEQ 1..25 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_017282" FT VAR_SEQ 1..21 FT /note="MSQSRHRAEAPPLEREDSGTF -> MQSTPFCGFC (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11230166" FT /id="VSP_017283" FT VARIANT 222 FT /note="P -> L (in DYT16; dbSNP:rs121434410)" FT /evidence="ECO:0000269|PubMed:18243799" FT /id="VAR_046213" FT MUTAGEN 18 FT /note="S->A: No effect on apoptosis induction under FT conditions of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 18 FT /note="S->D: Does not induce apoptosis." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 243 FT /note="Q->A: Abrogates apoptosis induction under conditions FT of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 246 FT /note="S->A: Abrogates apoptosis induction under conditions FT of stress and binding to EIF2AK2. Prevents activation of FT EIF2AK2 in stressed cells; when associated with A-287." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 246 FT /note="S->D: Induces activation of EIF2AK2 and apoptosis in FT unstressed cells; when associated with D-287." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 260 FT /note="D->A: Abrogates apoptosis induction under conditions FT of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 262 FT /note="D->A: Abrogates apoptosis induction under conditions FT of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 265 FT /note="S->A: Abrogates apoptosis induction under conditions FT of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 271 FT /note="Q->A: Abrogates apoptosis induction under conditions FT of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 279 FT /note="S->A: Abrogates apoptosis induction under conditions FT of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 287 FT /note="S->A: Abrogates apoptosis induction under conditions FT of stress. Prevents activation of EIF2AK2 in stressed FT cells; when associated with A-246." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 287 FT /note="S->D: Induces activation of EIF2AK2 and apoptosis in FT unstressed cells; when associated with D-246." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 288 FT /note="G->A: Abrogates apoptosis induction under conditions FT of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 291 FT /note="C->A: Abrogates apoptosis induction under conditions FT of stress." FT /evidence="ECO:0000269|PubMed:16982605" FT MUTAGEN 298..299 FT /note="AA->KK: Abrogates interaction with DICER1 but does FT not affect interaction with AGO2." FT /evidence="ECO:0000269|PubMed:16424907" FT CONFLICT 282 FT /note="T -> A (in Ref. 8; BAD96827)" FT /evidence="ECO:0000305" FT HELIX 35..45 FT /evidence="ECO:0007829|PDB:2DIX" FT STRAND 51..58 FT /evidence="ECO:0007829|PDB:2DIX" FT STRAND 60..63 FT /evidence="ECO:0007829|PDB:2DIX" FT STRAND 65..72 FT /evidence="ECO:0007829|PDB:2DIX" FT STRAND 75..79 FT /evidence="ECO:0007829|PDB:2DIX" FT HELIX 86..101 FT /evidence="ECO:0007829|PDB:2DIX" SQ SEQUENCE 313 AA; 34404 MW; 9B01637E6194827E CRC64; MSQSRHRAEA PPLEREDSGT FSLGKMITAK PGKTPIQVLH EYGMKTKNIP VYECERSDVQ IHVPTFTFRV TVGDITCTGE GTSKKLAKHR AAEAAINILK ANASICFAVP DPLMPDPSKQ PKNQLNPIGS LQELAIHHGW RLPEYTLSQE GGPAHKREYT TICRLESFME TGKGASKKQA KRNAAEKFLA KFSNISPENH ISLTNVVGHS LGCTWHSLRN SPGEKINLLK RSLLSIPNTD YIQLLSEIAK EQGFNITYLD IDELSANGQY QCLAELSTSP ITVCHGSGIS CGNAQSDAAH NALQYLKIIA ERK //