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O75807

- PR15A_HUMAN

UniProt

O75807 - PR15A_HUMAN

Protein

Protein phosphatase 1 regulatory subunit 15A

Gene

PPP1R15A

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 98 (01 Oct 2014)
      Sequence version 1 (01 Nov 1998)
      Previous versions | rss
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    Functioni

    Recruits the serine/threonine-protein phosphatase PP1 to dephosphorylate the translation initiation factor eIF-2A/EIF2S1, thereby reversing the shut-off of protein synthesis initiated by stress-inducible kinases and facilitating recovery of cells from stress. Down-regulates the TGF-beta signaling pathway by promoting dephosphorylation of TGFB1 by PP1. May promote apoptosis by inducing TP53 phosphorylation on 'Ser-15'.5 Publications

    GO - Molecular functioni

    1. protein binding Source: IntAct
    2. protein kinase binding Source: UniProtKB

    GO - Biological processi

    1. apoptotic process Source: ProtInc
    2. cell cycle arrest Source: ProtInc
    3. cellular response to DNA damage stimulus Source: ProtInc
    4. endoplasmic reticulum unfolded protein response Source: Ensembl
    5. negative regulation of transforming growth factor beta receptor signaling pathway Source: Reactome
    6. regulation of translation Source: UniProtKB-KW
    7. transforming growth factor beta receptor signaling pathway Source: Reactome

    Keywords - Biological processi

    Apoptosis, Stress response, Translation regulation

    Enzyme and pathway databases

    ReactomeiREACT_120727. Downregulation of TGF-beta receptor signaling.
    SignaLinkiO75807.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Protein phosphatase 1 regulatory subunit 15A
    Alternative name(s):
    Growth arrest and DNA damage-inducible protein GADD34
    Myeloid differentiation primary response protein MyD116 homolog
    Gene namesi
    Name:PPP1R15A
    Synonyms:GADD34
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 19

    Organism-specific databases

    HGNCiHGNC:14375. PPP1R15A.

    Subcellular locationi

    Endoplasmic reticulum 1 Publication

    GO - Cellular componenti

    1. cytosol Source: Reactome
    2. endoplasmic reticulum Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Endoplasmic reticulum

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi555 – 5584KVRF → AAAA: Reduces interaction with SMARCB1. 1 Publication
    Mutagenesisi556 – 5583VRF → ARA: Impairs PP1 activation. 1 Publication
    Mutagenesisi612 – 6121R → K: Reduces PP1-binding; when associated with K-614. 2 Publications
    Mutagenesisi614 – 6141R → K: Reduces PP1-binding; when associated with K-612. 2 Publications
    Mutagenesisi618 – 6181R → D: Reduces PP1-binding. 2 Publications

    Organism-specific databases

    PharmGKBiPA33632.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 674674Protein phosphatase 1 regulatory subunit 15APRO_0000320518Add
    BLAST

    Post-translational modificationi

    Phosphorylated on tyrosine by LYN; which impairs its antiproliferative activity.1 Publication

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    MaxQBiO75807.
    PaxDbiO75807.
    PRIDEiO75807.

    PTM databases

    PhosphoSiteiO75807.

    Expressioni

    Inductioni

    By methyl methanesulfonate and ionizing irradiation. By IL24/interleukin-24 in melanoma cells; which induces apoptosis.3 Publications

    Gene expression databases

    BgeeiO75807.
    CleanExiHS_PPP1R15A.
    GenevestigatoriO75807.

    Organism-specific databases

    HPAiCAB018395.
    HPA020240.

    Interactioni

    Subunit structurei

    Interacts with PCNA By similarity. Interacts with LYN and KMT2A/MLL1. Interacts with PP1, PPP1R1A and SMARCB1. Interacts with SMAD7. Interacts with BAG1.By similarity7 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    CTBP2P565452EBI-714746,EBI-741533
    PPP1R1AQ135224EBI-714746,EBI-1568511

    Protein-protein interaction databases

    BioGridi117172. 23 interactions.
    IntActiO75807. 12 interactions.
    MINTiMINT-1192304.
    STRINGi9606.ENSP00000200453.

    Structurei

    3D structure databases

    ProteinModelPortaliO75807.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Repeati337 – 369331Add
    BLAST
    Repeati384 – 417342Add
    BLAST
    Repeati427 – 460343Add
    BLAST
    Repeati477 – 510344Add
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni1 – 180180Required for localization in the endoplasmic reticulumAdd
    BLAST
    Regioni337 – 5101744 X 34 AA approximate repeatsAdd
    BLAST
    Regioni337 – 510174Interaction with SMAD7Add
    BLAST
    Regioni483 – 55573Interaction with KMT2A/MLL1Add
    BLAST
    Regioni536 – 58348Interaction with SMARCB1Add
    BLAST

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi112 – 1154Poly-Asp
    Compositional biasi160 – 503344Glu-richAdd
    BLAST
    Compositional biasi518 – 5214Poly-Pro
    Compositional biasi661 – 6666Poly-Ala

    Sequence similaritiesi

    Belongs to the PPP1R15 family.Curated

    Keywords - Domaini

    Repeat

    Phylogenomic databases

    eggNOGiNOG75356.
    HOGENOMiHOG000060154.
    HOVERGENiHBG052542.
    InParanoidiO75807.
    KOiK14019.
    OMAiWRDAHPF.
    OrthoDBiEOG75QR48.
    PhylomeDBiO75807.
    TreeFamiTF105547.

    Family and domain databases

    InterProiIPR019523. Prot_Pase1_reg-su15A/B_C.
    [Graphical view]
    PfamiPF10488. PP1c_bdg. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    O75807-1 [UniParc]FASTAAdd to Basket

    « Hide

    MAPGQAPHQA TPWRDAHPFF LLSPVMGLLS RAWSRLRGLG PLEPWLVEAV    50
    KGAALVEAGL EGEARTPLAI PHTPWGRRPE EEAEDSGGPG EDRETLGLKT 100
    SSSLPEAWGL LDDDDGMYGE REATSVPRGQ GSQFADGQRA PLSPSLLIRT 150
    LQGSDKNPGE EKAEEEGVAE EEGVNKFSYP PSHRECCPAV EEEDDEEAVK 200
    KEAHRTSTSA LSPGSKPSTW VSCPGEEENQ ATEDKRTERS KGARKTSVSP 250
    RSSGSDPRSW EYRSGEASEE KEEKAHKETG KGEAAPGPQS SAPAQRPQLK 300
    SWWCQPSDEE EGEVKALGAA EKDGEAECPP CIPPPSAFLK AWVYWPGEDT 350
    EEEEDEEEDE DSDSGSDEEE GEAEASSSTP ATGVFLKSWV YQPGEDTEEE 400
    EDEDSDTGSA EDEREAETSA STPPASAFLK AWVYRPGEDT EEEEDEDVDS 450
    EDKEDDSEAA LGEAESDPHP SHPDQRAHFR GWGYRPGKET EEEEAAEDWG 500
    EAEPCPFRVA IYVPGEKPPP PWAPPRLPLR LQRRLKRPET PTHDPDPETP 550
    LKARKVRFSE KVTVHFLAVW AGPAQAARQG PWEQLARDRS RFARRITQAQ 600
    EELSPCLTPA ARARAWARLR NPPLAPIPAL TQTLPSSSVP SSPVQTTPLS 650
    QAVATPSRSS AAAAAALDLS GRRG 674
    Length:674
    Mass (Da):73,478
    Last modified:November 1, 1998 - v1
    Checksum:iB257AA17456D1403
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti80 – 801E → G in BAA91649. (PubMed:14702039)Curated
    Sequence conflicti297 – 2971P → L in CAG33540. 1 PublicationCurated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti31 – 311R → H.
    Corresponds to variant rs564196 [ dbSNP | Ensembl ].
    VAR_039186
    Natural varianti32 – 321A → T.1 Publication
    Corresponds to variant rs3786734 [ dbSNP | Ensembl ].
    VAR_039187
    Natural varianti199 – 1991V → A.
    Corresponds to variant rs611251 [ dbSNP | Ensembl ].
    VAR_039188
    Natural varianti251 – 2511R → P.
    Corresponds to variant rs557806 [ dbSNP | Ensembl ].
    VAR_039189
    Natural varianti277 – 2771K → E.1 Publication
    Corresponds to variant rs610308 [ dbSNP | Ensembl ].
    VAR_039190
    Natural varianti312 – 3121G → S.1 Publication
    Corresponds to variant rs11541192 [ dbSNP | Ensembl ].
    VAR_062226
    Natural varianti316 – 3161A → P.1 Publication
    Corresponds to variant rs556052 [ dbSNP | Ensembl ].
    VAR_039191
    Natural varianti381 – 3811A → V.
    Corresponds to variant rs1050166 [ dbSNP | Ensembl ].
    VAR_039192
    Natural varianti476 – 4761R → S.1 Publication
    Corresponds to variant rs35087747 [ dbSNP | Ensembl ].
    VAR_039193
    Natural varianti594 – 5941R → C.
    Corresponds to variant rs2270946 [ dbSNP | Ensembl ].
    VAR_039194
    Natural varianti597 – 5971T → A.1 Publication
    Corresponds to variant rs500079 [ dbSNP | Ensembl ].
    VAR_039195

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U83981 mRNA. Translation: AAC25631.1.
    CR457259 mRNA. Translation: CAG33540.1.
    AK001361 mRNA. Translation: BAA91649.1.
    CH471177 Genomic DNA. Translation: EAW52409.1.
    BC003067 mRNA. Translation: AAH03067.1.
    CCDSiCCDS12738.1.
    RefSeqiNP_055145.3. NM_014330.3.
    UniGeneiHs.631593.

    Genome annotation databases

    EnsembliENST00000200453; ENSP00000200453; ENSG00000087074.
    GeneIDi23645.
    KEGGihsa:23645.
    UCSCiuc002pky.4. human.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U83981 mRNA. Translation: AAC25631.1 .
    CR457259 mRNA. Translation: CAG33540.1 .
    AK001361 mRNA. Translation: BAA91649.1 .
    CH471177 Genomic DNA. Translation: EAW52409.1 .
    BC003067 mRNA. Translation: AAH03067.1 .
    CCDSi CCDS12738.1.
    RefSeqi NP_055145.3. NM_014330.3.
    UniGenei Hs.631593.

    3D structure databases

    ProteinModelPortali O75807.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 117172. 23 interactions.
    IntActi O75807. 12 interactions.
    MINTi MINT-1192304.
    STRINGi 9606.ENSP00000200453.

    PTM databases

    PhosphoSitei O75807.

    Proteomic databases

    MaxQBi O75807.
    PaxDbi O75807.
    PRIDEi O75807.

    Protocols and materials databases

    DNASUi 23645.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000200453 ; ENSP00000200453 ; ENSG00000087074 .
    GeneIDi 23645.
    KEGGi hsa:23645.
    UCSCi uc002pky.4. human.

    Organism-specific databases

    CTDi 23645.
    GeneCardsi GC19P049375.
    H-InvDB HIX0015305.
    HIX0174313.
    HGNCi HGNC:14375. PPP1R15A.
    HPAi CAB018395.
    HPA020240.
    MIMi 611048. gene.
    neXtProti NX_O75807.
    PharmGKBi PA33632.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG75356.
    HOGENOMi HOG000060154.
    HOVERGENi HBG052542.
    InParanoidi O75807.
    KOi K14019.
    OMAi WRDAHPF.
    OrthoDBi EOG75QR48.
    PhylomeDBi O75807.
    TreeFami TF105547.

    Enzyme and pathway databases

    Reactomei REACT_120727. Downregulation of TGF-beta receptor signaling.
    SignaLinki O75807.

    Miscellaneous databases

    ChiTaRSi PPP1R15A. human.
    GeneWikii PPP1R15A.
    GenomeRNAii 23645.
    NextBioi 46457.
    PROi O75807.
    SOURCEi Search...

    Gene expression databases

    Bgeei O75807.
    CleanExi HS_PPP1R15A.
    Genevestigatori O75807.

    Family and domain databases

    InterProi IPR019523. Prot_Pase1_reg-su15A/B_C.
    [Graphical view ]
    Pfami PF10488. PP1c_bdg. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Mammalian GADD34, an apoptosis- and DNA damage-inducible gene."
      Hollander M.C., Zhan Q., Bae I., Fornace A.J. Jr.
      J. Biol. Chem. 272:13731-13737(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], INDUCTION.
    2. "Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)."
      Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.
      Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT THR-32.
    3. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANTS GLU-277; SER-312; PRO-316; SER-476 AND ALA-597.
    4. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    5. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Tissue: Brain.
    6. "The gadd and MyD genes define a novel set of mammalian genes encoding acidic proteins that synergistically suppress cell growth."
      Zhan Q., Lord K.A., Alamo I. Jr., Hollander M.C., Carrier F., Ron D., Kohn K.W., Hoffman B., Liebermann D.A., Fornace A.J. Jr.
      Mol. Cell. Biol. 14:2361-2371(1994) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    7. "Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins."
      Adler H.T., Chinery R., Wu D.Y., Kussick S.J., Payne J.M., Fornace A.J. Jr., Tkachuk D.C.
      Mol. Cell. Biol. 19:7050-7060(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH KMT2A/MLL1 AND SMARCB1, INDUCTION.
    8. "Interaction between growth arrest-DNA damage protein 34 and Src kinase Lyn negatively regulates genotoxic apoptosis."
      Grishin A.V., Azhipa O., Semenov I., Corey S.J.
      Proc. Natl. Acad. Sci. U.S.A. 98:10172-10177(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH LYN, PHOSPHORYLATION.
    9. "Growth arrest and DNA damage-inducible protein GADD34 assembles a novel signaling complex containing protein phosphatase 1 and inhibitor 1."
      Connor J.H., Weiser D.C., Li S., Hallenbeck J.M., Shenolikar S.
      Mol. Cell. Biol. 21:6841-6850(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH PP1 AND PPP1R1A, FUNCTION.
    10. "The human SNF5/INI1 protein facilitates the function of the growth arrest and DNA damage-inducible protein (GADD34) and modulates GADD34-bound protein phosphatase-1 activity."
      Wu D.Y., Tkachuck D.C., Roberson R.S., Schubach W.H.
      J. Biol. Chem. 277:27706-27715(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH SMARCB1 AND PP1, MUTAGENESIS OF 555-LYS--PHE-558.
    11. "mda-7 (IL-24) Mediates selective apoptosis in human melanoma cells by inducing the coordinated overexpression of the GADD family of genes by means of p38 MAPK."
      Sarkar D., Su Z.-Z., Lebedeva I.V., Sauane M., Gopalkrishnan R.V., Valerie K., Dent P., Fisher P.B.
      Proc. Natl. Acad. Sci. U.S.A. 99:10054-10059(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: INDUCTION.
    12. Cited for: FUNCTION.
    13. "Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2."
      Brush M.H., Weiser D.C., Shenolikar S.
      Mol. Cell. Biol. 23:1292-1303(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, MUTAGENESIS OF 556-VAL--SER-558; ARG-612; ARG-614 AND ARG-618, SUBCELLULAR LOCATION.
    14. "Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions."
      Hung W.J., Roberson R.S., Taft J., Wu D.Y.
      Mol. Cell. Biol. 23:3477-3486(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH BAG1.
    15. "GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor."
      Shi W., Sun C., He B., Xiong W., Shi X., Yao D., Cao X.
      J. Cell Biol. 164:291-300(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH SMAD7.
    16. "A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress."
      Boyce M., Bryant K.F., Jousse C., Long K., Harding H.P., Scheuner D., Kaufman R.J., Ma D., Coen D.M., Ron D., Yuan J.
      Science 307:935-939(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH PP1.

    Entry informationi

    Entry nameiPR15A_HUMAN
    AccessioniPrimary (citable) accession number: O75807
    Secondary accession number(s): Q6IA96, Q9NVU6
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: February 26, 2008
    Last sequence update: November 1, 1998
    Last modified: October 1, 2014
    This is version 98 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Miscellaneous

    The phosphatase activity of the PPP1R15A-PP1 complex toward EIF2S1 is specifically inhibited by Salubrinal, a drug that protects cells from endoplasmic reticulum stress.

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. Human chromosome 19
      Human chromosome 19: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3