PRKRA_HUMAN
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 03-AUG-2022, entry version 195.
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; Synonyms=PACT, RAX; 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 DDX58.
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 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 [29]
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 [30]
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). {ECO:0000250,
CC ECO:0000269|PubMed:10336432, ECO:0000269|PubMed:11238927,
CC ECO:0000269|PubMed:16424907, ECO:0000269|PubMed:16982605,
CC ECO:0000269|PubMed:17452327, 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 DDX58. {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 DDX58 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 -!- 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; O95786: DDX58; NbExp=5; IntAct=EBI-713955, EBI-995350;
CC O75569; Q9UPY3: DICER1; NbExp=8; 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=5; IntAct=EBI-713955, EBI-713507;
CC O75569; O15226: NKRF; NbExp=4; 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; O95793: STAU1; NbExp=3; IntAct=EBI-713955, EBI-358174;
CC O75569; Q96SI9: STRBP; NbExp=3; IntAct=EBI-713955, EBI-740355;
CC O75569; Q15633: TARBP2; NbExp=13; 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; P03416: N; Xeno; NbExp=6; IntAct=EBI-713955, EBI-25639341;
CC O75569; P0DTC9: N; Xeno; NbExp=4; 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}.
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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_003690.4. [O75569-1]
DR PDB; 2DIX; NMR; -; A=33-103.
DR PDBsum; 2DIX; -.
DR AlphaFoldDB; O75569; -.
DR SMR; O75569; -.
DR BioGRID; 114143; 383.
DR ComplexPortal; CPX-1072; RISC-loading complex, PRKRA variant.
DR DIP; DIP-41809N; -.
DR IntAct; O75569; 69.
DR MINT; O75569; -.
DR STRING; 9606.ENSP00000318176; -.
DR GlyGen; O75569; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O75569; -.
DR PhosphoSitePlus; O75569; -.
DR SwissPalm; O75569; -.
DR BioMuta; PRKRA; -.
DR CPTAC; CPTAC-994; -.
DR EPD; O75569; -.
DR jPOST; O75569; -.
DR MassIVE; O75569; -.
DR MaxQB; O75569; -.
DR PaxDb; O75569; -.
DR PeptideAtlas; O75569; -.
DR PRIDE; O75569; -.
DR ProteomicsDB; 50088; -. [O75569-1]
DR ProteomicsDB; 50089; -. [O75569-2]
DR ProteomicsDB; 50090; -. [O75569-3]
DR Antibodypedia; 3306; 374 antibodies from 35 providers.
DR DNASU; 8575; -.
DR Ensembl; ENST00000325748.9; ENSP00000318176.4; ENSG00000180228.14. [O75569-1]
DR Ensembl; ENST00000432031.6; ENSP00000393883.2; ENSG00000180228.14. [O75569-2]
DR Ensembl; ENST00000487082.5; ENSP00000430604.1; ENSG00000180228.14. [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 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 neXtProt; NX_O75569; -.
DR OpenTargets; ENSG00000180228; -.
DR Orphanet; 210571; Dystonia 16.
DR PharmGKB; PA33780; -.
DR VEuPathDB; HostDB:ENSG00000180228; -.
DR eggNOG; KOG3732; Eukaryota.
DR GeneTree; ENSGT00940000157618; -.
DR HOGENOM; CLU_048292_0_0_1; -.
DR InParanoid; O75569; -.
DR OMA; KKIAKHR; -.
DR OrthoDB; 1093169at2759; -.
DR PhylomeDB; O75569; -.
DR TreeFam; TF315953; -.
DR PathwayCommons; O75569; -.
DR Reactome; R-HSA-203927; MicroRNA (miRNA) biogenesis.
DR Reactome; R-HSA-426486; Small interfering RNA (siRNA) biogenesis.
DR SignaLink; O75569; -.
DR SIGNOR; O75569; -.
DR BioGRID-ORCS; 8575; 373 hits in 1087 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 208 other tissues.
DR ExpressionAtlas; O75569; baseline and differential.
DR Genevisible; O75569; HS.
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; TAS:ProtInc.
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: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:0006468; P:protein phosphorylation; IEA:Ensembl.
DR GO; GO:0050821; P:protein stabilization; IMP:BHF-UCL.
DR GO; GO:0070920; P:regulation of production of small RNA involved in gene silencing by RNA; IBA:GO_Central.
DR GO; GO:0009615; P:response to virus; TAS:ProtInc.
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 InterPro; IPR014720; dsRBD_dom.
DR InterPro; IPR033363; PRKRA.
DR InterPro; IPR044465; PRKRA_DSRM_1.
DR InterPro; IPR044466; PRKRA_DSRM_2.
DR InterPro; IPR044467; PRKRA_DSRM_3.
DR InterPro; IPR032478; Staufen_C.
DR PANTHER; PTHR46205:SF2; PTHR46205:SF2; 1.
DR Pfam; PF00035; dsrm; 2.
DR Pfam; PF16482; Staufen_C; 1.
DR SMART; SM00358; DSRM; 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; Reference proteome;
KW Repeat; RNA-binding; 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 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
