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O75807

- PR15A_HUMAN

UniProt

O75807 - PR15A_HUMAN

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Protein
Protein phosphatase 1 regulatory subunit 15A
Gene
PPP1R15A, GADD34
Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

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
Complete GO annotation...

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
Complete GO annotation...

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
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
Complete GO annotation...

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. 1 Publication
Mutagenesisi614 – 6141R → K: Reduces PP1-binding; when associated with K-612. 1 Publication
Mutagenesisi618 – 6181R → D: Reduces PP1-binding. 1 Publication

Organism-specific databases

PharmGKBiPA33632.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 674674Protein phosphatase 1 regulatory subunit 15A
PRO_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 BAG1.7 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.

Family & Domainsi

Domains and Repeats

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

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni1 – 180180Required for localization in the endoplasmic reticulum
Add
BLAST
Regioni337 – 5101744 X 34 AA approximate repeats
Add
BLAST
Regioni337 – 510174Interaction with SMAD7
Add
BLAST
Regioni483 – 55573Interaction with KMT2A/MLL1
Add
BLAST
Regioni536 – 58348Interaction with SMARCB1
Add
BLAST

Compositional bias

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

Sequence similaritiesi

Belongs to the PPP1R15 family.

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

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 conflict

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

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...

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

« Hide 'large scale' publications
  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: September 3, 2014
This is version 97 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

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