O75807 (PR15A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	PPP1R15A
Synonyms:	GADD34

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	674 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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'. Ref.6 Ref.9 Ref.12 Ref.13 Ref.15
Subunit structure	Interacts with PCNA By similarity. Interacts with LYN and MLL. Interacts with PP1, PPP1R1A and SMARCB1. Interacts with SMAD7. Interacts with BAG1. Ref.7 Ref.8 Ref.9 Ref.10 Ref.14 Ref.15 Ref.16
Subcellular location	Endoplasmic reticulum Ref.13.
Induction	By methyl methanesulfonate and ionizing irradiation. By IL24/interleukin-24 in melanoma cells; which induces apoptosis. Ref.1 Ref.7 Ref.11
Post-translational modification	Phosphorylated on tyrosine by LYN; which impairs its antiproliferative activity. Ref.8
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.
Sequence similarities	Belongs to the PPP1R15 family.

Ontologies

Keywords
Biological process	Apoptosis Stress response Translation regulation
Cellular component	Endoplasmic reticulum
Coding sequence diversity	Polymorphism
Domain	Repeat
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process Traceable author statement Ref.1. Source: ProtInc cell cycle arrest Traceable author statement Ref.1. Source: ProtInc endoplasmic reticulum unfolded protein response Inferred from electronic annotation. Source: Compara negative regulation of transforming growth factor beta receptor signaling pathway Traceable author statement. Source: Reactome regulation of translation Inferred from electronic annotation. Source: UniProtKB-KW response to DNA damage stimulus Traceable author statement Ref.1. Source: ProtInc transforming growth factor beta receptor signaling pathway Traceable author statement. Source: Reactome
Cellular_component	cytosol Traceable author statement. Source: Reactome endoplasmic reticulum Inferred from electronic annotation. Source: UniProtKB-SubCell
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CTBP2	P56545	2	EBI-714746,EBI-741533
PPP1R1A	Q13522	4	EBI-714746,EBI-1568511

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 674	674	Protein phosphatase 1 regulatory subunit 15A		PRO_0000320518
Regions
	Repeat	337 – 369	33	1
	Repeat	384 – 417	34	2
	Repeat	427 – 460	34	3
	Repeat	477 – 510	34	4
	Region	1 – 180	180	Required for localization in the endoplasmic reticulum
	Region	337 – 510	174	4 X 34 AA approximate repeats
	Region	337 – 510	174	Interaction with SMAD7
	Region	483 – 555	73	Interaction with MLL
	Region	536 – 583	48	Interaction with SMARCB1
	Compositional bias	112 – 115	4	Poly-Asp
	Compositional bias	160 – 503	344	Glu-rich
	Compositional bias	518 – 521	4	Poly-Pro
	Compositional bias	661 – 666	6	Poly-Ala
Natural variations
	Natural variant	31	1	R → H. Corresponds to variant rs564196 [ dbSNP | Ensembl ].		VAR_039186
	Natural variant	32	1	A → T. Ref.2 Corresponds to variant rs3786734 [ dbSNP | Ensembl ].		VAR_039187
	Natural variant	199	1	V → A. Corresponds to variant rs611251 [ dbSNP | Ensembl ].		VAR_039188
	Natural variant	251	1	R → P. Corresponds to variant rs557806 [ dbSNP | Ensembl ].		VAR_039189
	Natural variant	277	1	K → E. Ref.3 Corresponds to variant rs610308 [ dbSNP | Ensembl ].		VAR_039190
	Natural variant	312	1	G → S. Ref.3 Corresponds to variant rs11541192 [ dbSNP | Ensembl ].		VAR_062226
	Natural variant	316	1	A → P. Ref.3 Corresponds to variant rs556052 [ dbSNP | Ensembl ].		VAR_039191
	Natural variant	381	1	A → V. Corresponds to variant rs1050166 [ dbSNP | Ensembl ].		VAR_039192
	Natural variant	476	1	R → S. Ref.3 Corresponds to variant rs35087747 [ dbSNP | Ensembl ].		VAR_039193
	Natural variant	594	1	R → C. Corresponds to variant rs2270946 [ dbSNP | Ensembl ].		VAR_039194
	Natural variant	597	1	T → A. Ref.3 Corresponds to variant rs500079 [ dbSNP | Ensembl ].		VAR_039195
Experimental info
	Mutagenesis	555 – 558	4	KVRF → AAAA: Reduces interaction with SMARCB1. Ref.10
	Mutagenesis	556 – 558	3	VRF → ARA: Impairs PP1 activation. Ref.13
	Mutagenesis	612	1	R → K: Reduces PP1-binding; when associated with K-614. Ref.13
	Mutagenesis	614	1	R → K: Reduces PP1-binding; when associated with K-612. Ref.13
	Mutagenesis	618	1	R → D: Reduces PP1-binding. Ref.13
	Sequence conflict	80	1	E → G in BAA91649. Ref.3
	Sequence conflict	297	1	P → L in CAG33540. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	O75807 [UniParc]. Last modified November 1, 1998. Version 1. Checksum: B257AA17456D1403	FASTA	674	73,478
	10 20 30 40 50 60 MAPGQAPHQA TPWRDAHPFF LLSPVMGLLS RAWSRLRGLG PLEPWLVEAV KGAALVEAGL 70 80 90 100 110 120 EGEARTPLAI PHTPWGRRPE EEAEDSGGPG EDRETLGLKT SSSLPEAWGL LDDDDGMYGE 130 140 150 160 170 180 REATSVPRGQ GSQFADGQRA PLSPSLLIRT LQGSDKNPGE EKAEEEGVAE EEGVNKFSYP 190 200 210 220 230 240 PSHRECCPAV EEEDDEEAVK KEAHRTSTSA LSPGSKPSTW VSCPGEEENQ ATEDKRTERS 250 260 270 280 290 300 KGARKTSVSP RSSGSDPRSW EYRSGEASEE KEEKAHKETG KGEAAPGPQS SAPAQRPQLK 310 320 330 340 350 360 SWWCQPSDEE EGEVKALGAA EKDGEAECPP CIPPPSAFLK AWVYWPGEDT EEEEDEEEDE 370 380 390 400 410 420 DSDSGSDEEE GEAEASSSTP ATGVFLKSWV YQPGEDTEEE EDEDSDTGSA EDEREAETSA 430 440 450 460 470 480 STPPASAFLK AWVYRPGEDT EEEEDEDVDS EDKEDDSEAA LGEAESDPHP SHPDQRAHFR 490 500 510 520 530 540 GWGYRPGKET EEEEAAEDWG EAEPCPFRVA IYVPGEKPPP PWAPPRLPLR LQRRLKRPET 550 560 570 580 590 600 PTHDPDPETP LKARKVRFSE KVTVHFLAVW AGPAQAARQG PWEQLARDRS RFARRITQAQ 610 620 630 640 650 660 EELSPCLTPA ARARAWARLR NPPLAPIPAL TQTLPSSSVP SSPVQTTPLS QAVATPSRSS 670 AAAAAALDLS GRRG

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases 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 MLL 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]	"GADD34 induces p53 phosphorylation and p21/WAF1 transcription." Yagi A., Hasegawa Y., Xiao H., Haneda M., Kojima E., Nishikimi A., Hasegawa T., Shimokata K., Isobe K. J. Cell. Biochem. 90:1242-1249(2003) [PubMed] [Europe PMC] [Abstract] 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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	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.
IPI	IPI00290444.
RefSeq	NP_055145.3. NM_014330.3.
UniGene	Hs.631593.
3D structure databases
ProteinModelPortal	O75807.
ModBase	Search...
Protein-protein interaction databases
IntAct	O75807. 9 interactions.
MINT	MINT-1192304.
STRING	9606.ENSP00000200453.
PTM databases
PhosphoSite	O75807.
Proteomic databases
PaxDb	O75807.
PRIDE	O75807.
Protocols and materials databases
DNASU	23645.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000200453; ENSP00000200453; ENSG00000087074.
GeneID	23645.
KEGG	hsa:23645.
UCSC	uc002pky.4. human.
Organism-specific databases
CTD	23645.
GeneCards	GC19P049375.
H-InvDB	HIX0015305. HIX0174313.
HGNC	HGNC:14375. PPP1R15A.
HPA	CAB018395. HPA020240.
MIM	611048. gene.
neXtProt	NX_O75807.
PharmGKB	PA33632.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG75356.
HOGENOM	HOG000060154.
HOVERGEN	HBG052542.
InParanoid	O75807.
KO	K14019.
OMA	AWVYRPG.
OrthoDB	EOG4Q84XN.
PhylomeDB	O75807.
Enzyme and pathway databases
Pathway_Interaction_DB	bmppathway. BMP receptor signaling. tgfbrpathway. TGF-beta receptor signaling.
Reactome	REACT_111102. Signal Transduction.
Gene expression databases
Bgee	O75807.
CleanEx	HS_PPP1R15A.
Genevestigator	O75807.
Family and domain databases
InterPro	IPR019523. Prot_Pase1_reg-su15A/B_C. [Graphical view]
Pfam	PF10488. PP1c_bdg. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	PPP1R15A. human.
GenomeRNAi	23645.
NextBio	46457.
SOURCE	Search...

Entry information

Entry name

PR15A_HUMAN

Accession

Primary (citable) accession number: O75807
Secondary accession number(s): Q6IA96, Q9NVU6

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 26, 2008
Last sequence update:	November 1, 1998
Last modified:	April 3, 2013
This is version 85 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.