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Protein

Protein phosphatase 1 regulatory subunit 15A

Gene

PPP1R15A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: 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

  • protein kinase binding Source: UniProtKB
  • protein phosphatase 1 binding Source: ParkinsonsUK-UCL
  • protein phosphatase type 1 activator activity Source: ParkinsonsUK-UCL
  • protein phosphatase type 1 regulator activity Source: ParkinsonsUK-UCL

GO - Biological processi

Complete GO annotation...

Keywords - Biological processi

Apoptosis, Stress response, Translation regulation

Enzyme and pathway databases

ReactomeiR-HSA-2173788. Downregulation of TGF-beta receptor signaling.
SignaLinkiO75807.
SIGNORiO75807.

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
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

HGNCiHGNC:14375. PPP1R15A.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 21Cytoplasmic1 PublicationAdd BLAST21
Intramembranei22 – 39Helical1 PublicationAdd BLAST18
Topological domaini40 – 674Cytoplasmic1 PublicationAdd BLAST635

GO - Cellular componenti

  • cytoplasm Source: ParkinsonsUK-UCL
  • cytosol Source: Reactome
  • endoplasmic reticulum Source: ParkinsonsUK-UCL
  • endoplasmic reticulum membrane Source: ParkinsonsUK-UCL
  • Golgi apparatus Source: ParkinsonsUK-UCL
  • membrane Source: ParkinsonsUK-UCL
  • mitochondrial outer membrane Source: UniProtKB-SubCell
  • mitochondrion Source: ParkinsonsUK-UCL
  • protein phosphatase type 1 complex Source: ParkinsonsUK-UCL
Complete GO annotation...

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane, Mitochondrion, Mitochondrion outer membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi25V → R: Localizes to cytoplasm, degraded more slowly. 1 Publication1
Mutagenesisi29L → R: Localizes to cytoplasm. 1 Publication1
Mutagenesisi262Y → F: Significantly reduced turnover. 1 Publication1
Mutagenesisi555 – 558KVRF → AAAA: Reduces interaction with SMARCB1. 1 Publication4
Mutagenesisi556 – 558VRF → ARA: Impairs PP1 activation. 1 Publication3
Mutagenesisi612R → K: Reduces PP1-binding; when associated with K-614. 1 Publication1
Mutagenesisi614R → K: Reduces PP1-binding; when associated with K-612. 1 Publication1
Mutagenesisi618R → D: Reduces PP1-binding. 1 Publication1

Organism-specific databases

DisGeNETi23645.
OpenTargetsiENSG00000087074.
PharmGKBiPA33632.

Polymorphism and mutation databases

BioMutaiPPP1R15A.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00003205181 – 674Protein phosphatase 1 regulatory subunit 15AAdd BLAST674

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei143PhosphoserineCombined sources1
Modified residuei262Phosphotyrosine1 Publication1
Modified residuei391Phosphotyrosine1 Publication1
Modified residuei434Phosphotyrosine1 Publication1
Modified residuei512Phosphotyrosine1 Publication1

Post-translational modificationi

Phosphorylated at multiple Ser/Thr residues. Phosphorylated on tyrosine by LYN; which impairs its antiproliferative activity. Phosphorylation at Tyr-262 enhances proteasomal degradation, this position is dephosphorylated by PTPN2.2 Publications
Polyubiquitinated. Exhibits a rapid proteasomal degradation with a half-life under 1 hour, ubiquitination depends on endoplasmic reticulum association.1 Publication

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiO75807.
PaxDbiO75807.
PeptideAtlasiO75807.
PRIDEiO75807.

PTM databases

iPTMnetiO75807.
PhosphoSitePlusiO75807.

Expressioni

Inductioni

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

Gene expression databases

BgeeiENSG00000087074.
CleanExiHS_PPP1R15A.
ExpressionAtlasiO75807. baseline and differential.
GenevisibleiO75807. HS.

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

GO - Molecular functioni

  • protein kinase binding Source: UniProtKB
  • protein phosphatase 1 binding Source: ParkinsonsUK-UCL

Protein-protein interaction databases

BioGridi117172. 30 interactors.
IntActiO75807. 12 interactors.
MINTiMINT-1192304.
STRINGi9606.ENSP00000200453.

Structurei

Secondary structure

1674
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi563 – 565Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4XPNX-ray2.29B/D552-591[»]
ProteinModelPortaliO75807.
SMRiO75807.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati337 – 3691Add BLAST33
Repeati384 – 4172Add BLAST34
Repeati427 – 4603Add BLAST34
Repeati477 – 5104Add BLAST34

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 60Required for localization in the endoplasmic reticulumAdd BLAST60
Regioni337 – 5104 X 34 AA approximate repeatsAdd BLAST174
Regioni337 – 510Interaction with SMAD71 PublicationAdd BLAST174
Regioni483 – 555Interaction with KMT2A/MLL1Add BLAST73
Regioni536 – 583Interaction with SMARCB1Add BLAST48

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi112 – 115Poly-Asp4
Compositional biasi160 – 503Glu-richAdd BLAST344
Compositional biasi518 – 521Poly-Pro4
Compositional biasi661 – 666Poly-Ala6

Sequence similaritiesi

Belongs to the PPP1R15 family.Curated

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiENOG410ITE6. Eukaryota.
ENOG410Y1YJ. LUCA.
GeneTreeiENSGT00510000049287.
HOGENOMiHOG000060154.
HOVERGENiHBG052542.
InParanoidiO75807.
KOiK14019.
OMAiVRAWVYR.
OrthoDBiEOG091G19MD.
PhylomeDBiO75807.
TreeFamiTF105547.

Family and domain databases

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

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O75807-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAPGQAPHQA TPWRDAHPFF LLSPVMGLLS RAWSRLRGLG PLEPWLVEAV
60 70 80 90 100
KGAALVEAGL EGEARTPLAI PHTPWGRRPE EEAEDSGGPG EDRETLGLKT
110 120 130 140 150
SSSLPEAWGL LDDDDGMYGE REATSVPRGQ GSQFADGQRA PLSPSLLIRT
160 170 180 190 200
LQGSDKNPGE EKAEEEGVAE EEGVNKFSYP PSHRECCPAV EEEDDEEAVK
210 220 230 240 250
KEAHRTSTSA LSPGSKPSTW VSCPGEEENQ ATEDKRTERS KGARKTSVSP
260 270 280 290 300
RSSGSDPRSW EYRSGEASEE KEEKAHKETG KGEAAPGPQS SAPAQRPQLK
310 320 330 340 350
SWWCQPSDEE EGEVKALGAA EKDGEAECPP CIPPPSAFLK AWVYWPGEDT
360 370 380 390 400
EEEEDEEEDE DSDSGSDEEE GEAEASSSTP ATGVFLKSWV YQPGEDTEEE
410 420 430 440 450
EDEDSDTGSA EDEREAETSA STPPASAFLK AWVYRPGEDT EEEEDEDVDS
460 470 480 490 500
EDKEDDSEAA LGEAESDPHP SHPDQRAHFR GWGYRPGKET EEEEAAEDWG
510 520 530 540 550
EAEPCPFRVA IYVPGEKPPP PWAPPRLPLR LQRRLKRPET PTHDPDPETP
560 570 580 590 600
LKARKVRFSE KVTVHFLAVW AGPAQAARQG PWEQLARDRS RFARRITQAQ
610 620 630 640 650
EELSPCLTPA ARARAWARLR NPPLAPIPAL TQTLPSSSVP SSPVQTTPLS
660 670
QAVATPSRSS AAAAAALDLS GRRG
Length:674
Mass (Da):73,478
Last modified:November 1, 1998 - v1
Checksum:iB257AA17456D1403
GO
Isoform 2 (identifier: O75807-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     16-16: A → D
     17-175: Missing.

Note: No experimental confirmation available.
Show »
Length:515
Mass (Da):56,515
Checksum:i1411EE8095E602B0
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti80E → G in BAA91649 (PubMed:14702039).Curated1
Sequence conflicti297P → L in CAG33540 (Ref. 2) Curated1
Sequence conflicti669L → P in BAG59265 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_03918631R → H.Corresponds to variant rs564196dbSNPEnsembl.1
Natural variantiVAR_03918732A → T.1 PublicationCorresponds to variant rs3786734dbSNPEnsembl.1
Natural variantiVAR_039188199V → A.Corresponds to variant rs611251dbSNPEnsembl.1
Natural variantiVAR_039189251R → P.Corresponds to variant rs557806dbSNPEnsembl.1
Natural variantiVAR_039190277K → E.1 PublicationCorresponds to variant rs610308dbSNPEnsembl.1
Natural variantiVAR_062226312G → S.1 PublicationCorresponds to variant rs11541192dbSNPEnsembl.1
Natural variantiVAR_039191316A → P.1 PublicationCorresponds to variant rs556052dbSNPEnsembl.1
Natural variantiVAR_039192381A → V.Corresponds to variant rs1050166dbSNPEnsembl.1
Natural variantiVAR_039193476R → S.1 PublicationCorresponds to variant rs35087747dbSNPEnsembl.1
Natural variantiVAR_039194594R → C.Corresponds to variant rs2270946dbSNPEnsembl.1
Natural variantiVAR_039195597T → A.1 PublicationCorresponds to variant rs500079dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_05708316A → D in isoform 2. 1 Publication1
Alternative sequenceiVSP_05708417 – 175Missing in isoform 2. 1 PublicationAdd BLAST159

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U83981 mRNA. Translation: AAC25631.1.
CR457259 mRNA. Translation: CAG33540.1.
AK001361 mRNA. Translation: BAA91649.1.
AK296668 mRNA. Translation: BAG59265.1.
CH471177 Genomic DNA. Translation: EAW52409.1.
BC003067 mRNA. Translation: AAH03067.1.
CCDSiCCDS12738.1. [O75807-1]
RefSeqiNP_055145.3. NM_014330.3. [O75807-1]
UniGeneiHs.631593.

Genome annotation databases

EnsembliENST00000200453; ENSP00000200453; ENSG00000087074. [O75807-1]
GeneIDi23645.
KEGGihsa:23645.
UCSCiuc002pky.5. human. [O75807-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U83981 mRNA. Translation: AAC25631.1.
CR457259 mRNA. Translation: CAG33540.1.
AK001361 mRNA. Translation: BAA91649.1.
AK296668 mRNA. Translation: BAG59265.1.
CH471177 Genomic DNA. Translation: EAW52409.1.
BC003067 mRNA. Translation: AAH03067.1.
CCDSiCCDS12738.1. [O75807-1]
RefSeqiNP_055145.3. NM_014330.3. [O75807-1]
UniGeneiHs.631593.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4XPNX-ray2.29B/D552-591[»]
ProteinModelPortaliO75807.
SMRiO75807.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi117172. 30 interactors.
IntActiO75807. 12 interactors.
MINTiMINT-1192304.
STRINGi9606.ENSP00000200453.

PTM databases

iPTMnetiO75807.
PhosphoSitePlusiO75807.

Polymorphism and mutation databases

BioMutaiPPP1R15A.

Proteomic databases

MaxQBiO75807.
PaxDbiO75807.
PeptideAtlasiO75807.
PRIDEiO75807.

Protocols and materials databases

DNASUi23645.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000200453; ENSP00000200453; ENSG00000087074. [O75807-1]
GeneIDi23645.
KEGGihsa:23645.
UCSCiuc002pky.5. human. [O75807-1]

Organism-specific databases

CTDi23645.
DisGeNETi23645.
GeneCardsiPPP1R15A.
H-InvDBHIX0015305.
HIX0174313.
HGNCiHGNC:14375. PPP1R15A.
HPAiCAB018395.
HPA020240.
MIMi611048. gene.
neXtProtiNX_O75807.
OpenTargetsiENSG00000087074.
PharmGKBiPA33632.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410ITE6. Eukaryota.
ENOG410Y1YJ. LUCA.
GeneTreeiENSGT00510000049287.
HOGENOMiHOG000060154.
HOVERGENiHBG052542.
InParanoidiO75807.
KOiK14019.
OMAiVRAWVYR.
OrthoDBiEOG091G19MD.
PhylomeDBiO75807.
TreeFamiTF105547.

Enzyme and pathway databases

ReactomeiR-HSA-2173788. Downregulation of TGF-beta receptor signaling.
SignaLinkiO75807.
SIGNORiO75807.

Miscellaneous databases

ChiTaRSiPPP1R15A. human.
GeneWikiiPPP1R15A.
GenomeRNAii23645.
PROiO75807.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000087074.
CleanExiHS_PPP1R15A.
ExpressionAtlasiO75807. baseline and differential.
GenevisibleiO75807. HS.

Family and domain databases

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

Entry informationi

Entry nameiPR15A_HUMAN
AccessioniPrimary (citable) accession number: O75807
Secondary accession number(s): B4DKQ3, Q6IA96, Q9NVU6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 26, 2008
Last sequence update: November 1, 1998
Last modified: November 2, 2016
This is version 120 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

3D-structure, 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. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.