PR15A_HUMAN
ID PR15A_HUMAN Reviewed; 674 AA.
AC O75807; B4DKQ3; Q6IA96; Q9NVU6;
DT 26-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1998, sequence version 1.
DT 03-AUG-2022, entry version 151.
DE RecName: Full=Protein phosphatase 1 regulatory subunit 15A;
DE AltName: Full=Growth arrest and DNA damage-inducible protein GADD34;
DE AltName: Full=Myeloid differentiation primary response protein MyD116 homolog;
GN Name=PPP1R15A; Synonyms=GADD34;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND INDUCTION.
RX PubMed=9153226; DOI=10.1074/jbc.272.21.13731;
RA Hollander M.C., Zhan Q., Bae I., Fornace A.J. Jr.;
RT "Mammalian GADD34, an apoptosis- and DNA damage-inducible gene.";
RL J. Biol. Chem. 272:13731-13737(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT THR-32.
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANTS
RP GLU-277; SER-312; PRO-316; SER-476 AND ALA-597.
RC TISSUE=Umbilical cord blood;
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].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 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 [6]
RP FUNCTION.
RX PubMed=8139541; DOI=10.1128/mcb.14.4.2361-2371.1994;
RA Zhan Q., Lord K.A., Alamo I. Jr., Hollander M.C., Carrier F., Ron D.,
RA Kohn K.W., Hoffman B., Liebermann D.A., Fornace A.J. Jr.;
RT "The gadd and MyD genes define a novel set of mammalian genes encoding
RT acidic proteins that synergistically suppress cell growth.";
RL Mol. Cell. Biol. 14:2361-2371(1994).
RN [7]
RP INTERACTION WITH KMT2A/MLL1 AND SMARCB1, AND INDUCTION.
RX PubMed=10490642; DOI=10.1128/mcb.19.10.7050;
RA Adler H.T., Chinery R., Wu D.Y., Kussick S.J., Payne J.M.,
RA Fornace A.J. Jr., Tkachuk D.C.;
RT "Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and
RT associate with the GADD34 and hSNF5/INI1 proteins.";
RL Mol. Cell. Biol. 19:7050-7060(1999).
RN [8]
RP INTERACTION WITH LYN, AND PHOSPHORYLATION.
RX PubMed=11517336; DOI=10.1073/pnas.191130798;
RA Grishin A.V., Azhipa O., Semenov I., Corey S.J.;
RT "Interaction between growth arrest-DNA damage protein 34 and Src kinase Lyn
RT negatively regulates genotoxic apoptosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:10172-10177(2001).
RN [9]
RP INTERACTION WITH PP1 AND PPP1R1A, AND FUNCTION.
RX PubMed=11564868; DOI=10.1128/mcb.21.20.6841-6850.2001;
RA Connor J.H., Weiser D.C., Li S., Hallenbeck J.M., Shenolikar S.;
RT "Growth arrest and DNA damage-inducible protein GADD34 assembles a novel
RT signaling complex containing protein phosphatase 1 and inhibitor 1.";
RL Mol. Cell. Biol. 21:6841-6850(2001).
RN [10]
RP INTERACTION WITH SMARCB1 AND PPP1R1A, AND MUTAGENESIS OF 555-LYS--PHE-558.
RX PubMed=12016208; DOI=10.1074/jbc.m200955200;
RA Wu D.Y., Tkachuck D.C., Roberson R.S., Schubach W.H.;
RT "The human SNF5/INI1 protein facilitates the function of the growth arrest
RT and DNA damage-inducible protein (GADD34) and modulates GADD34-bound
RT protein phosphatase-1 activity.";
RL J. Biol. Chem. 277:27706-27715(2002).
RN [11]
RP INDUCTION.
RX PubMed=12114539; DOI=10.1073/pnas.152327199;
RA Sarkar D., Su Z.-Z., Lebedeva I.V., Sauane M., Gopalkrishnan R.V.,
RA Valerie K., Dent P., Fisher P.B.;
RT "mda-7 (IL-24) Mediates selective apoptosis in human melanoma cells by
RT inducing the coordinated overexpression of the GADD family of genes by
RT means of p38 MAPK.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:10054-10059(2002).
RN [12]
RP FUNCTION.
RX PubMed=14635196; DOI=10.1002/jcb.10711;
RA Yagi A., Hasegawa Y., Xiao H., Haneda M., Kojima E., Nishikimi A.,
RA Hasegawa T., Shimokata K., Isobe K.;
RT "GADD34 induces p53 phosphorylation and p21/WAF1 transcription.";
RL J. Cell. Biochem. 90:1242-1249(2003).
RN [13]
RP FUNCTION, MUTAGENESIS OF 556-VAL--SER-558; ARG-612; ARG-614 AND ARG-618,
RP AND SUBCELLULAR LOCATION.
RX PubMed=12556489; DOI=10.1128/mcb.23.4.1292-1303.2003;
RA Brush M.H., Weiser D.C., Shenolikar S.;
RT "Growth arrest and DNA damage-inducible protein GADD34 targets protein
RT phosphatase 1 alpha to the endoplasmic reticulum and promotes
RT dephosphorylation of the alpha subunit of eukaryotic translation initiation
RT factor 2.";
RL Mol. Cell. Biol. 23:1292-1303(2003).
RN [14]
RP INTERACTION WITH BAG1.
RX PubMed=12724406; DOI=10.1128/mcb.23.10.3477-3486.2003;
RA Hung W.J., Roberson R.S., Taft J., Wu D.Y.;
RT "Human BAG-1 proteins bind to the cellular stress response protein GADD34
RT and interfere with GADD34 functions.";
RL Mol. Cell. Biol. 23:3477-3486(2003).
RN [15]
RP FUNCTION, AND INTERACTION WITH SMAD7.
RX PubMed=14718519; DOI=10.1083/jcb.200307151;
RA Shi W., Sun C., He B., Xiong W., Shi X., Yao D., Cao X.;
RT "GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor.";
RL J. Cell Biol. 164:291-300(2004).
RN [16]
RP INTERACTION WITH PPP1CA.
RX PubMed=15705855; DOI=10.1126/science.1101902;
RA Boyce M., Bryant K.F., Jousse C., Long K., Harding H.P., Scheuner D.,
RA Kaufman R.J., Ma D., Coen D.M., Ron D., Yuan J.;
RT "A selective inhibitor of eIF2alpha dephosphorylation protects cells from
RT ER stress.";
RL Science 307:935-939(2005).
RN [17]
RP INDUCTION.
RX PubMed=19131336; DOI=10.1074/jbc.m806735200;
RA Lee Y.Y., Cevallos R.C., Jan E.;
RT "An upstream open reading frame regulates translation of GADD34 during
RT cellular stresses that induce eIF2alpha phosphorylation.";
RL J. Biol. Chem. 284:6661-6673(2009).
RN [18]
RP SUBCELLULAR LOCATION, TOPOLOGY, INTRAMEMBRANE REGION, AND MUTAGENESIS OF
RP VAL-25 AND LEU-29.
RX PubMed=21518769; DOI=10.1074/jbc.m110.212787;
RA Zhou W., Brush M.H., Choy M.S., Shenolikar S.;
RT "Association with endoplasmic reticulum promotes proteasomal degradation of
RT GADD34 protein.";
RL J. Biol. Chem. 286:21687-21696(2011).
RN [19]
RP PHOSPHORYLATION AT TYR-262; TYR-391; TYR-434 AND TYR-512, UBIQUITINATION,
RP AND MUTAGENESIS OF TYR-262.
RX PubMed=24092754; DOI=10.1074/jbc.m113.504407;
RA Zhou W., Jeyaraman K., Yusoff P., Shenolikar S.;
RT "Phosphorylation at tyrosine 262 promotes GADD34 protein turnover.";
RL J. Biol. Chem. 288:33146-33155(2013).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-143, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [21]
RP FUNCTION, INTERACTION WITH NOX4, AND SUBCELLULAR LOCATION.
RX PubMed=26742780; DOI=10.15252/embj.201592394;
RA Santos C.X., Hafstad A.D., Beretta M., Zhang M., Molenaar C., Kopec J.,
RA Fotinou D., Murray T.V., Cobb A.M., Martin D., Zeh Silva M., Anilkumar N.,
RA Schroeder K., Shanahan C.M., Brewer A.C., Brandes R.P., Blanc E.,
RA Parsons M., Belousov V., Cammack R., Hider R.C., Steiner R.A., Shah A.M.;
RT "Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates
RT eIF2alpha-mediated stress signaling.";
RL EMBO J. 35:319-334(2016).
RN [22]
RP FUNCTION, AND INDUCTION BY HIV-1 VIRUS.
RX PubMed=31778897; DOI=10.1016/j.virol.2019.11.010;
RA Ishaq M., Marshall H., Natarajan V.;
RT "GADD34 attenuates HIV-1 replication by viral 5'-UTR TAR RNA-mediated
RT translational inhibition.";
RL Virology 540:119-131(2020).
RN [23]
RP FUNCTION.
RX PubMed=32978159; DOI=10.1126/sciadv.abb0205;
RA Gambardella G., Staiano L., Moretti M.N., De Cegli R., Fagnocchi L.,
RA Di Tullio G., Polletti S., Braccia C., Armirotti A., Zippo A., Ballabio A.,
RA De Matteis M.A., di Bernardo D.;
RT "GADD34 is a modulator of autophagy during starvation.";
RL Sci. Adv. 6:0-0(2020).
RN [24]
RP FUNCTION (MICROBIAL INFECTION), INDUCTION BY ENTEROVIRUS 71, INTERACTION
RP WITH ENTEROVIRUS 71 PROTEIN 3CD (MICROBIAL INFECTION), AND SUBCELLULAR
RP LOCATION.
RX PubMed=34985336; DOI=10.1128/spectrum.01388-21;
RA Li H., Li W., Zhang S., Qiu M., Li Z., Lin Y., Tan J., Qiao W.;
RT "Enterovirus 71 Activates GADD34 via Precursor 3CD to Promote IRES-Mediated
RT Viral Translation.";
RL Microbiol. Spectr. 0:0-0(2022).
RN [25] {ECO:0007744|PDB:4XPN}
RP X-RAY CRYSTALLOGRAPHY (2.29 ANGSTROMS) OF 552-591 IN COMPLEX WITH PPP1CA
RP AND EIF2S1, AND FUNCTION.
RX PubMed=26095357; DOI=10.1016/j.celrep.2015.05.043;
RA Choy M.S., Yusoff P., Lee I.C., Newton J.C., Goh C.W., Page R.,
RA Shenolikar S., Peti W.;
RT "Structural and Functional Analysis of the GADD34:PP1 eIF2alpha
RT Phosphatase.";
RL Cell Rep. 11:1885-1891(2015).
CC -!- FUNCTION: Recruits the serine/threonine-protein phosphatase PPP1CA to
CC prevents excessive phosphorylation of the translation initiation factor
CC eIF-2A/EIF2S1, thereby reversing the shut-off of protein synthesis
CC initiated by stress-inducible kinases and facilitating recovery of
CC cells from stress (PubMed:26742780, PubMed:26095357). Down-regulates
CC the TGF-beta signaling pathway by promoting dephosphorylation of TGFB1
CC by PP1 (PubMed:14718519). May promote apoptosis by inducing p53/TP53
CC phosphorylation on 'Ser-15' (PubMed:14635196). Plays an essential role
CC in autophagy by tuning translation during starvation, thus enabling
CC lysosomal biogenesis and a sustained autophagic flux (PubMed:32978159).
CC Acts also a viral restriction factor by attenuating HIV-1 replication
CC (PubMed:31778897). Mechanistically, mediates the inhibition of HIV-1
CC TAR RNA-mediated translation (PubMed:31778897).
CC {ECO:0000269|PubMed:11564868, ECO:0000269|PubMed:12556489,
CC ECO:0000269|PubMed:14635196, ECO:0000269|PubMed:14718519,
CC ECO:0000269|PubMed:26095357, ECO:0000269|PubMed:31778897,
CC ECO:0000269|PubMed:8139541}.
CC -!- FUNCTION: (Microbial infection) Promotes enterovirus 71 replication by
CC mediating the internal ribosome entry site (IRES) activity of viral 5'-
CC UTR. {ECO:0000269|PubMed:34985336}.
CC -!- SUBUNIT: Interacts with PPP1CA (PubMed:15705855, PubMed:26095357).
CC Interacts with EIF2S1 (PubMed:26095357). Interacts with PCNA (By
CC similarity). Interacts with LYN and KMT2A/MLL1 (PubMed:11517336).
CC Interacts with PPP1R1A and SMARCB1 (PubMed:12016208). Interacts with
CC SMAD7 (PubMed:14718519). Interacts with BAG1 (PubMed:12724406).
CC Interacts with NOX4 (PubMed:26742780). {ECO:0000250,
CC ECO:0000269|PubMed:10490642, ECO:0000269|PubMed:11517336,
CC ECO:0000269|PubMed:11564868, ECO:0000269|PubMed:12016208,
CC ECO:0000269|PubMed:12724406, ECO:0000269|PubMed:14718519,
CC ECO:0000269|PubMed:15705855, ECO:0000269|PubMed:26095357,
CC ECO:0000269|PubMed:26742780}.
CC -!- SUBUNIT: (Microbial infection) Interacts with enterovirus 71/EV71 non-
CC structural protein precursor 3CD; this interaction promotes EV71
CC replication. {ECO:0000269|PubMed:34985336}.
CC -!- INTERACTION:
CC O75807; P56545: CTBP2; NbExp=2; IntAct=EBI-714746, EBI-741533;
CC O75807; P62136: PPP1CA; NbExp=12; IntAct=EBI-714746, EBI-357253;
CC O75807; Q13522: PPP1R1A; NbExp=4; IntAct=EBI-714746, EBI-1568511;
CC O75807; Q13148: TARDBP; NbExp=10; IntAct=EBI-714746, EBI-372899;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Peripheral
CC membrane protein; Cytoplasmic side {ECO:0000269|PubMed:12556489,
CC ECO:0000269|PubMed:21518769, ECO:0000269|PubMed:26742780}.
CC Mitochondrion outer membrane; Peripheral membrane protein; Cytoplasmic
CC side {ECO:0000269|PubMed:21518769}. Note=Associates with membranes via
CC an N-terminal amphipathic intramembrane region.
CC {ECO:0000269|PubMed:21518769}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O75807-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O75807-2; Sequence=VSP_057083, VSP_057084;
CC -!- INDUCTION: Specifically produced in response to stress: in absence of
CC stress, some upstream open reading frame (uORF) of this transcript is
CC translated, thereby preventing its translation (PubMed:19131336). By
CC methyl methanesulfonate and ionizing irradiation (PubMed:9153226). By
CC IL24/interleukin-24 in melanoma cells; which induces apoptosis
CC (PubMed:10490642, PubMed:12114539). By viral infection including
CC enterovirus 71/EV71 or HIV-1 (PubMed:34985336,PubMed:31778897).
CC {ECO:0000269|PubMed:10490642, ECO:0000269|PubMed:12114539,
CC ECO:0000269|PubMed:19131336, ECO:0000269|PubMed:34985336,
CC ECO:0000269|PubMed:9153226}.
CC -!- PTM: Phosphorylated at multiple Ser/Thr residues. Phosphorylated on
CC tyrosine by LYN; which impairs its antiproliferative activity.
CC Phosphorylation at Tyr-262 enhances proteasomal degradation, this
CC position is dephosphorylated by PTPN2. {ECO:0000269|PubMed:11517336,
CC ECO:0000269|PubMed:24092754}.
CC -!- PTM: Polyubiquitinated. Exhibits a rapid proteasomal degradation with a
CC half-life under 1 hour, ubiquitination depends on endoplasmic reticulum
CC association. {ECO:0000269|PubMed:24092754}.
CC -!- MISCELLANEOUS: The phosphatase activity of the PPP1R15A-PP1 complex
CC toward EIF2S1 is specifically inhibited by Salubrinal, a drug that
CC protects cells from endoplasmic reticulum stress.
CC -!- SIMILARITY: Belongs to the PPP1R15 family. {ECO:0000305}.
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DR EMBL; U83981; AAC25631.1; -; mRNA.
DR EMBL; CR457259; CAG33540.1; -; mRNA.
DR EMBL; AK001361; BAA91649.1; -; mRNA.
DR EMBL; AK296668; BAG59265.1; -; mRNA.
DR EMBL; CH471177; EAW52409.1; -; Genomic_DNA.
DR EMBL; BC003067; AAH03067.1; -; mRNA.
DR CCDS; CCDS12738.1; -. [O75807-1]
DR RefSeq; NP_055145.3; NM_014330.3. [O75807-1]
DR PDB; 4XPN; X-ray; 2.29 A; B/D=552-591.
DR PDB; 7NXV; X-ray; 2.55 A; C/E=582-621.
DR PDB; 7NZM; EM; 3.96 A; C=553-624.
DR PDBsum; 4XPN; -.
DR PDBsum; 7NXV; -.
DR PDBsum; 7NZM; -.
DR AlphaFoldDB; O75807; -.
DR SMR; O75807; -.
DR BioGRID; 117172; 36.
DR IntAct; O75807; 204.
DR MINT; O75807; -.
DR STRING; 9606.ENSP00000200453; -.
DR BindingDB; O75807; -.
DR ChEMBL; CHEMBL4630805; -.
DR iPTMnet; O75807; -.
DR PhosphoSitePlus; O75807; -.
DR BioMuta; PPP1R15A; -.
DR jPOST; O75807; -.
DR MassIVE; O75807; -.
DR MaxQB; O75807; -.
DR PaxDb; O75807; -.
DR PeptideAtlas; O75807; -.
DR PRIDE; O75807; -.
DR ProteomicsDB; 50202; -. [O75807-1]
DR Antibodypedia; 4340; 305 antibodies from 34 providers.
DR DNASU; 23645; -.
DR Ensembl; ENST00000200453.6; ENSP00000200453.4; ENSG00000087074.8. [O75807-1]
DR GeneID; 23645; -.
DR KEGG; hsa:23645; -.
DR MANE-Select; ENST00000200453.6; ENSP00000200453.4; NM_014330.5; NP_055145.3.
DR UCSC; uc002pky.5; human. [O75807-1]
DR CTD; 23645; -.
DR DisGeNET; 23645; -.
DR GeneCards; PPP1R15A; -.
DR HGNC; HGNC:14375; PPP1R15A.
DR HPA; ENSG00000087074; Tissue enhanced (bone).
DR MIM; 611048; gene.
DR neXtProt; NX_O75807; -.
DR OpenTargets; ENSG00000087074; -.
DR PharmGKB; PA33632; -.
DR VEuPathDB; HostDB:ENSG00000087074; -.
DR eggNOG; ENOG502S745; Eukaryota.
DR GeneTree; ENSGT00940000154404; -.
DR HOGENOM; CLU_028812_0_0_1; -.
DR InParanoid; O75807; -.
DR OMA; VRAWVYR; -.
DR OrthoDB; 391948at2759; -.
DR PhylomeDB; O75807; -.
DR TreeFam; TF105547; -.
DR PathwayCommons; O75807; -.
DR Reactome; R-HSA-2173788; Downregulation of TGF-beta receptor signaling.
DR Reactome; R-HSA-9648895; Response of EIF2AK1 (HRI) to heme deficiency.
DR SignaLink; O75807; -.
DR SIGNOR; O75807; -.
DR BioGRID-ORCS; 23645; 26 hits in 1084 CRISPR screens.
DR ChiTaRS; PPP1R15A; human.
DR GeneWiki; PPP1R15A; -.
DR GenomeRNAi; 23645; -.
DR Pharos; O75807; Tchem.
DR PRO; PR:O75807; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; O75807; protein.
DR Bgee; ENSG00000087074; Expressed in mucosa of stomach and 193 other tissues.
DR ExpressionAtlas; O75807; baseline and differential.
DR Genevisible; O75807; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; NAS:ParkinsonsUK-UCL.
DR GO; GO:0005794; C:Golgi apparatus; IDA:ParkinsonsUK-UCL.
DR GO; GO:0016020; C:membrane; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:ParkinsonsUK-UCL.
DR GO; GO:0000164; C:protein phosphatase type 1 complex; IDA:ParkinsonsUK-UCL.
DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR GO; GO:0008157; F:protein phosphatase 1 binding; IDA:ParkinsonsUK-UCL.
DR GO; GO:0072542; F:protein phosphatase activator activity; IC:ParkinsonsUK-UCL.
DR GO; GO:0019888; F:protein phosphatase regulator activity; IBA:GO_Central.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; TAS:ProtInc.
DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; TAS:ParkinsonsUK-UCL.
DR GO; GO:1903898; P:negative regulation of PERK-mediated unfolded protein response; TAS:ParkinsonsUK-UCL.
DR GO; GO:0032515; P:negative regulation of phosphoprotein phosphatase activity; IDA:ParkinsonsUK-UCL.
DR GO; GO:0035308; P:negative regulation of protein dephosphorylation; IDA:ParkinsonsUK-UCL.
DR GO; GO:1903917; P:positive regulation of endoplasmic reticulum stress-induced eIF2 alpha dephosphorylation; IDA:ParkinsonsUK-UCL.
DR GO; GO:1902310; P:positive regulation of peptidyl-serine dephosphorylation; IDA:ParkinsonsUK-UCL.
DR GO; GO:0032516; P:positive regulation of phosphoprotein phosphatase activity; IDA:ParkinsonsUK-UCL.
DR GO; GO:0032058; P:positive regulation of translational initiation in response to stress; IC:ParkinsonsUK-UCL.
DR GO; GO:0070972; P:protein localization to endoplasmic reticulum; IMP:ParkinsonsUK-UCL.
DR GO; GO:0051726; P:regulation of cell cycle; TAS:ProtInc.
DR GO; GO:0036496; P:regulation of translational initiation by eIF2 alpha dephosphorylation; IDA:ParkinsonsUK-UCL.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IDA:ParkinsonsUK-UCL.
DR DisProt; DP01203; -.
DR InterPro; IPR019523; Prot_Pase1_reg-su15A/B_C.
DR Pfam; PF10488; PP1c_bdg; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; Endoplasmic reticulum;
KW Membrane; Mitochondrion; Mitochondrion outer membrane; Phosphoprotein;
KW Reference proteome; Repeat; Stress response; Translation regulation;
KW Ubl conjugation.
FT CHAIN 1..674
FT /note="Protein phosphatase 1 regulatory subunit 15A"
FT /id="PRO_0000320518"
FT TOPO_DOM 1..21
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:21518769"
FT INTRAMEM 22..39
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:21518769"
FT TOPO_DOM 40..674
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:21518769"
FT REPEAT 337..369
FT /note="1"
FT REPEAT 384..417
FT /note="2"
FT REPEAT 427..460
FT /note="3"
FT REPEAT 477..510
FT /note="4"
FT REGION 1..60
FT /note="Required for localization in the endoplasmic
FT reticulum"
FT REGION 65..504
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 337..510
FT /note="4 X 34 AA approximate repeats"
FT REGION 337..510
FT /note="Interaction with SMAD7"
FT /evidence="ECO:0000269|PubMed:14718519"
FT REGION 483..555
FT /note="Interaction with KMT2A/MLL1"
FT REGION 534..554
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 536..583
FT /note="Interaction with SMARCB1"
FT REGION 625..674
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 75..92
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 126..152
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 205..226
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 228..245
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 262..281
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 306..322
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 348..374
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 395..411
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 438..461
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 462..492
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 630..658
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 143
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 262
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:24092754"
FT MOD_RES 391
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:24092754"
FT MOD_RES 434
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:24092754"
FT MOD_RES 512
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:24092754"
FT VAR_SEQ 16
FT /note="A -> D (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_057083"
FT VAR_SEQ 17..175
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_057084"
FT VARIANT 31
FT /note="R -> H (in dbSNP:rs564196)"
FT /id="VAR_039186"
FT VARIANT 32
FT /note="A -> T (in dbSNP:rs3786734)"
FT /evidence="ECO:0000269|Ref.2"
FT /id="VAR_039187"
FT VARIANT 199
FT /note="V -> A (in dbSNP:rs611251)"
FT /id="VAR_039188"
FT VARIANT 251
FT /note="R -> P (in dbSNP:rs557806)"
FT /id="VAR_039189"
FT VARIANT 277
FT /note="K -> E (in dbSNP:rs610308)"
FT /evidence="ECO:0000269|PubMed:14702039"
FT /id="VAR_039190"
FT VARIANT 312
FT /note="G -> S (in dbSNP:rs11541192)"
FT /evidence="ECO:0000269|PubMed:14702039"
FT /id="VAR_062226"
FT VARIANT 316
FT /note="A -> P (in dbSNP:rs556052)"
FT /evidence="ECO:0000269|PubMed:14702039"
FT /id="VAR_039191"
FT VARIANT 381
FT /note="A -> V (in dbSNP:rs1050166)"
FT /id="VAR_039192"
FT VARIANT 476
FT /note="R -> S (in dbSNP:rs35087747)"
FT /evidence="ECO:0000269|PubMed:14702039"
FT /id="VAR_039193"
FT VARIANT 594
FT /note="R -> C (in dbSNP:rs2270946)"
FT /id="VAR_039194"
FT VARIANT 597
FT /note="T -> A (in dbSNP:rs500079)"
FT /evidence="ECO:0000269|PubMed:14702039"
FT /id="VAR_039195"
FT MUTAGEN 25
FT /note="V->R: Localizes to cytoplasm, degraded more slowly."
FT /evidence="ECO:0000269|PubMed:21518769"
FT MUTAGEN 29
FT /note="L->R: Localizes to cytoplasm."
FT /evidence="ECO:0000269|PubMed:21518769"
FT MUTAGEN 262
FT /note="Y->F: Significantly reduced turnover."
FT /evidence="ECO:0000269|PubMed:24092754"
FT MUTAGEN 555..558
FT /note="KVRF->AAAA: Reduces interaction with SMARCB1."
FT /evidence="ECO:0000269|PubMed:12016208"
FT MUTAGEN 556..558
FT /note="VRF->ARA: Impairs PP1 activation."
FT /evidence="ECO:0000269|PubMed:12556489"
FT MUTAGEN 612
FT /note="R->K: Reduces PP1-binding; when associated with K-
FT 614."
FT /evidence="ECO:0000269|PubMed:12556489"
FT MUTAGEN 614
FT /note="R->K: Reduces PP1-binding; when associated with K-
FT 612."
FT /evidence="ECO:0000269|PubMed:12556489"
FT MUTAGEN 618
FT /note="R->D: Reduces PP1-binding."
FT /evidence="ECO:0000269|PubMed:12556489"
FT CONFLICT 80
FT /note="E -> G (in Ref. 3; BAA91649)"
FT /evidence="ECO:0000305"
FT CONFLICT 297
FT /note="P -> L (in Ref. 2; CAG33540)"
FT /evidence="ECO:0000305"
FT CONFLICT 669
FT /note="L -> P (in Ref. 3; BAG59265)"
FT /evidence="ECO:0000305"
FT STRAND 563..565
FT /evidence="ECO:0007829|PDB:4XPN"
FT HELIX 583..602
FT /evidence="ECO:0007829|PDB:7NXV"
FT HELIX 604..606
FT /evidence="ECO:0007829|PDB:7NXV"
FT HELIX 609..618
FT /evidence="ECO:0007829|PDB:7NXV"
SQ SEQUENCE 674 AA; 73478 MW; B257AA17456D1403 CRC64;
MAPGQAPHQA TPWRDAHPFF LLSPVMGLLS RAWSRLRGLG PLEPWLVEAV KGAALVEAGL
EGEARTPLAI PHTPWGRRPE EEAEDSGGPG EDRETLGLKT SSSLPEAWGL LDDDDGMYGE
REATSVPRGQ GSQFADGQRA PLSPSLLIRT LQGSDKNPGE EKAEEEGVAE EEGVNKFSYP
PSHRECCPAV EEEDDEEAVK KEAHRTSTSA LSPGSKPSTW VSCPGEEENQ ATEDKRTERS
KGARKTSVSP RSSGSDPRSW EYRSGEASEE KEEKAHKETG KGEAAPGPQS SAPAQRPQLK
SWWCQPSDEE EGEVKALGAA EKDGEAECPP CIPPPSAFLK AWVYWPGEDT EEEEDEEEDE
DSDSGSDEEE GEAEASSSTP ATGVFLKSWV YQPGEDTEEE EDEDSDTGSA EDEREAETSA
STPPASAFLK AWVYRPGEDT EEEEDEDVDS EDKEDDSEAA LGEAESDPHP SHPDQRAHFR
GWGYRPGKET EEEEAAEDWG EAEPCPFRVA IYVPGEKPPP PWAPPRLPLR LQRRLKRPET
PTHDPDPETP LKARKVRFSE KVTVHFLAVW AGPAQAARQG PWEQLARDRS RFARRITQAQ
EELSPCLTPA ARARAWARLR NPPLAPIPAL TQTLPSSSVP SSPVQTTPLS QAVATPSRSS
AAAAAALDLS GRRG
