P67775 (PP2AA_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
Short name=PP2A-alpha
EC=3.1.3.16

Alternative name(s):
Replication protein C
Short name=RP-C

Gene names

Name:

PPP2CA

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	309 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	PP2A can modulate the activity of phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase. Cooperates with SGOL2 to protect centromeric cohesin from separase-mediated cleavage in oocytes specifically during meiosis I By similarity. Can dephosphorylate SV40 large T antigen and p53/TP53. Dephosphorylates SV40 large T antigen, preferentially on serine residues 120, 123, 677, and perhaps 679. The C subunit was most active, followed by the AC form, which was more active than the ABC form, and activity of all three forms was strongly stimulated by manganese, and to a lesser extent by magnesium. Dephosphorylation by the AC form, but not C or ABC form is inhibited by small T antigen. Activates RAF1 by dephosphorylating it at 'Ser-259'. Ref.10 Ref.11
Catalytic activity	A phosphoprotein + H2O = a protein + phosphate.
Cofactor	Binds 1 iron ion per subunit By similarity. Binds 1 manganese ion per subunit By similarity.
Subunit structure	PP2A consists of a common heterodimeric core enzyme, composed of PPP2CA a 36 kDa catalytic subunit (subunit C) and PPP2R1A a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Interacts with NXN; the interaction is direct By similarity. Interacts with TP53, SGOL1 and SGOL2. Interacts with AXIN1; the interaction dephosphorylates AXIN1. Interacts with PIM3; this interaction promotes dephosphorylation, ubiquitination and proteasomal degradation of PIM3. Interacts with RAF1. Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16
Subcellular location	Cytoplasm. Nucleus. Chromosome › centromere. Cytoplasm › cytoskeleton › spindle pole. Note: In prometaphase cells, but not in anaphase cells, localizes at centromeres. During mitosis, also found at spindle poles. Centromeric localization requires the presence of SGOL2 By similarity. Ref.13
Post-translational modification	Reversibly methyl esterified on Leu-309. Carboxyl methylation may play a role in holoenzyme assembly, enhancing the affinity of the PP2A core enzyme for some, but not all, regulatory subunits. It varies during the cell cycle. Phosphorylation of either threonine (by autophosphorylation-activated protein kinase) or tyrosine results in inactivation of the phosphatase. Auto-dephosphorylation has been suggested as a mechanism for reactivation.
Sequence similarities	Belongs to the PPP phosphatase family. PP-1 subfamily.

Ontologies

Keywords
Biological process	Meiosis
Cellular component	Centromere Chromosome Cytoplasm Cytoskeleton Nucleus
Coding sequence diversity	Polymorphism
Ligand	Iron Manganese Metal-binding
Molecular function	Hydrolase Protein phosphatase
PTM	Acetylation Methylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	RNA splicing Non-traceable author statement. Source: UniProtKB ceramide metabolic process Non-traceable author statement. Source: UniProtKB inactivation of MAPK activity Non-traceable author statement. Source: UniProtKB induction of apoptosis Traceable author statement. Source: UniProtKB mRNA metabolic process Traceable author statement. Source: Reactome meiosis Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of cell growth Non-traceable author statement. Source: UniProtKB negative regulation of epithelial to mesenchymal transition Inferred from mutant phenotype. Source: BHF-UCL negative regulation of tyrosine phosphorylation of Stat3 protein Non-traceable author statement. Source: UniProtKB positive regulation of protein serine/threonine kinase activity Inferred from mutant phenotype. Source: BHF-UCL protein dephosphorylation Traceable author statement Ref.1. Source: UniProtKB regulation of DNA replication Non-traceable author statement. Source: UniProtKB regulation of Wnt receptor signaling pathway Non-traceable author statement. Source: UniProtKB regulation of cell adhesion Non-traceable author statement. Source: UniProtKB regulation of transcription, DNA-dependent Non-traceable author statement. Source: UniProtKB response to organic substance Non-traceable author statement. Source: UniProtKB second-messenger-mediated signaling Non-traceable author statement. Source: UniProtKB
Cellular component	chromosome, centromeric region Inferred from electronic annotation. Source: UniProtKB-SubCell cytosol Traceable author statement. Source: UniProtKB mitochondrion Non-traceable author statement. Source: UniProtKB nucleus Non-traceable author statement. Source: UniProtKB protein phosphatase type 2A complex Inferred from direct assay. Source: UniProtKB soluble fraction Non-traceable author statement. Source: UniProtKB spindle pole Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW phosphoprotein phosphatase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
IGBP1	P78318	9	EBI-712311,EBI-1055954
PPP2R1A	P30153	14	EBI-712311,EBI-302388
PPP2R1B	P30154	6	EBI-712311,EBI-357094
STRN	O43815	3	EBI-712311,EBI-1046642
TRIP13	Q15645	3	EBI-712311,EBI-358993

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 309

309

Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform

PRO_0000058839

Sites

Active site

118

1

Proton donor By similarity

Metal binding

57

1

Iron By similarity

Metal binding

59

1

Iron By similarity

Metal binding

85

1

Iron By similarity

Metal binding

85

1

Manganese By similarity

Metal binding

117

1

Manganese By similarity

Metal binding

167

1

Manganese By similarity

Metal binding

241

1

Manganese By similarity

Amino acid modifications

Modified residue

1

1

N-acetylmethionine Ref.17

Modified residue

4

1

N6-acetyllysine Ref.17

Modified residue

307

1

Phosphotyrosine Ref.8

Modified residue

309

1

Leucine methyl ester Ref.6

Natural variations

Natural variant

52

1

V → A.
Corresponds to variant rs11552681 [ dbSNP | Ensembl ].

VAR_051735

Experimental info

Mutagenesis

309

1

L → A: Loss of binding to PP2A B-alpha regulatory subunit. Ref.7

Secondary structure

1

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309

Helix Strand Turn

Details...

Helix

7 – 17

11

Turn

18 – 20

3

Helix

25 – 41

17

Beta strand

46 – 48

3

Beta strand

50 – 55

6

Helix

62 – 72

11

Turn

75 – 77

3

Beta strand

80 – 82

3

Beta strand

87 – 91

5

Helix

93 – 106

14

Turn

108 – 110

3

Beta strand

111 – 113

3

Helix

121 – 124

4

Helix

129 – 136

8

Beta strand

137 – 140

4

Helix

141 – 150

10

Beta strand

157 – 159

3

Turn

160 – 162

3

Beta strand

163 – 165

3

Helix

177 – 181

5

Beta strand

191 – 193

3

Helix

194 – 200

7

Beta strand

205 – 211

7

Beta strand

215 – 220

6

Helix

222 – 231

10

Beta strand

235 – 239

5

Beta strand

247 – 251

5

Turn

252 – 255

4

Beta strand

256 – 259

4

Helix

265 – 267

3

Beta strand

273 – 278

6

Beta strand

284 – 289

6

Sequences

	Sequence		Length	Mass (Da)
	P67775 [UniParc]. Last modified October 11, 2004. Version 1. Checksum: C602291F78F34555	FASTA	309	35,594
	10 20 30 40 50 60 MDEKVFTKEL DQWIEQLNEC KQLSESQVKS LCEKAKEILT KESNVQEVRC PVTVCGDVHG 70 80 90 100 110 120 QFHDLMELFR IGGKSPDTNY LFMGDYVDRG YYSVETVTLL VALKVRYRER ITILRGNHES 130 140 150 160 170 180 RQITQVYGFY DECLRKYGNA NVWKYFTDLF DYLPLTALVD GQIFCLHGGL SPSIDTLDHI 190 200 210 220 230 240 RALDRLQEVP HEGPMCDLLW SDPDDRGGWG ISPRGAGYTF GQDISETFNH ANGLTLVSRA 250 260 270 280 290 300 HQLVMEGYNW CHDRNVVTIF SAPNYCYRCG NQAAIMELDD TLKYSFLQFD PAPRRGEPHV TRRTPDYFL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The nucleotide sequence of the cDNA encoding the human lung protein phosphatase 2A alpha catalytic subunit." Stone S.R., Mayer R., Wernet W., Maurer F., Hofsteenge J., Hemmings B.A. Nucleic Acids Res. 16:11365-11365(1988) [PubMed: 2849764] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Fibroblast.
[2]	"Human liver phosphatase 2A: cDNA and amino acid sequence of two catalytic subunit isotypes." Arino J., Woon C.W., Brautigan D.L., Miller T.B. Jr., Johnson G.L. Proc. Natl. Acad. Sci. U.S.A. 85:4252-4256(1988) [PubMed: 2837763] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver.
[3]	"Structure and transcriptional regulation of protein phosphatase 2A catalytic subunit genes." Khew-Goodall Y., Mayer R.E., Maurer F., Stone S.R., Hemmings B.A. Biochemistry 30:89-97(1991) [PubMed: 1846293] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lung, Placenta and Uterus.
[5]	"Dephosphorylation of simian virus 40 large-T antigen and p53 protein by protein phosphatase 2A: inhibition by small-t antigen." Scheidtmann K.H., Mumby M.C., Rundell K., Walter G. Mol. Cell. Biol. 11:1996-2003(1991) [PubMed: 1848668] [Abstract] Cited for: DEPHOSPHORYLATION OF SV40 LARGE-T ANTIGEN AND P53 PROTEIN.
[6]	"The catalytic subunit of protein phosphatase 2A is carboxyl-methylated in vivo." Favre B., Zolnierowicz S., Turowski P., Hemmings B.A. J. Biol. Chem. 269:16311-16317(1994) [PubMed: 8206937] [Abstract] Cited for: METHYLATION AT LEU-309.
[7]	"Methylated C-terminal leucine residue of PP2A catalytic subunit is important for binding of regulatory Balpha subunit." Bryant J.C., Westphal R.S., Wadzinski B.E. Biochem. J. 339:241-246(1999) [PubMed: 10191253] [Abstract] Cited for: MUTAGENESIS OF LEU-309.
[8]	"Protein phosphatase 2A dephosphorylates simian virus 40 large T antigen specifically at residues involved in regulation of DNA-binding activity." Scheidtmann K.H., Virshup D.M., Kelly T.J. J. Virol. 65:2098-2101(1991) [PubMed: 1848320] [Abstract] Cited for: SITES OF DEPHOSPHORYLATION AT SV40 LARGE-T ANTIGEN.
[9]	"Activation of SV40 DNA replication in vitro by cellular protein phosphatase 2A." Virshup D.M., Kauffman M.G., Kelly T.J. EMBO J. 8:3891-3898(1989) [PubMed: 2555176] [Abstract] Cited for: PARTIAL PROTEIN SEQUENCE, ACTIVATION OF SV40 REPLICATION.
[10]	"Identification of a domain of Axin that binds to the serine/threonine protein phosphatase 2A and a self-binding domain." Hsu W., Zeng L., Costantini F. J. Biol. Chem. 274:3439-3445(1999) [PubMed: 9920888] [Abstract] Cited for: INTERACTION WITH AXIN1, FUNCTION.
[11]	"Raf-1-associated protein phosphatase 2A as a positive regulator of kinase activation." Abraham D., Podar K., Pacher M., Kubicek M., Welzel N., Hemmings B.A., Dilworth S.M., Mischak H., Kolch W., Baccarini M. J. Biol. Chem. 275:22300-22304(2000) [PubMed: 10801873] [Abstract] Cited for: FUNCTION, INTERACTION WITH RAF1.
[12]	"PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation." Tang Z., Shu H., Qi W., Mahmood N.A., Mumby M.C., Yu H. Dev. Cell 10:575-585(2006) [PubMed: 16580887] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY, INTERACTION WITH SGOL1.
[13]	"Shugoshin collaborates with protein phosphatase 2A to protect cohesin." Kitajima T.S., Sakuno T., Ishiguro K., Iemura S., Natsume T., Kawashima S.A., Watanabe Y. Nature 441:46-52(2006) [PubMed: 16541025] [Abstract] Cited for: SUBCELLULAR LOCATION, INTERACTION WITH SGOL1.
[14]	"Protein phosphatase 2A regulates the stability of Pim protein kinases." Losman J.A., Chen X.P., Vuong B.Q., Fay S., Rothman P.B. J. Biol. Chem. 278:4800-4805(2003) [PubMed: 12473674] [Abstract] Cited for: INTERACTION WITH PIM3.
[15]	"A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55." Li H.H., Cai X., Shouse G.P., Piluso L.G., Liu X. EMBO J. 26:402-411(2007) [PubMed: 17245430] [Abstract] Cited for: INTERACTION WITH TP53.
[16]	"Tripin/hSgo2 recruits MCAK to the inner centromere to correct defective kinetochore attachments." Huang H., Feng J., Famulski J., Rattner J.B., Liu S.T., Kao G.D., Muschel R., Chan G.K., Yen T.J. J. Cell Biol. 177:413-424(2007) [PubMed: 17485487] [Abstract] Cited for: INTERACTION WITH SGOL2.
[17]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1; LYS-4, MASS SPECTROMETRY.
[18]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[19]	"Structural mechanism of demethylation and inactivation of protein phosphatase 2A." Xing Y., Li Z., Chen Y., Stock J.B., Jeffrey P.D., Shi Y. Cell 133:154-163(2008) [PubMed: 18394995] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) IN COMPLEX WITH PPP2R1A AND PPME1.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X12646 mRNA. Translation: CAA31176.1.
J03804 mRNA. Translation: AAB38019.1.
M60483 Genomic DNA. Translation: AAA36466.1.
BC000400 mRNA. Translation: AAH00400.1.
BC002657 mRNA. Translation: AAH02657.1.
BC019275 mRNA. Translation: AAH19275.1.
BC031696 mRNA. Translation: AAH31696.1.

IPI

IPI00008380.

PIR

PAHU2A. S01986.

RefSeq

NP_002706.1. NM_002715.2.

UniGene

Hs.105818.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2IAE	X-ray	3.50	C/F	1-309	[»]
2IE3	X-ray	2.80	C	1-309	[»]
2IE4	X-ray	2.60	C	1-309	[»]
2NPP	X-ray	3.30	C/F	1-309	[»]
2NYL	X-ray	3.80	C/F	2-294	[»]
2NYM	X-ray	3.60	C/F	2-294	[»]
3C5W	X-ray	2.80	C	1-309	[»]
3DW8	X-ray	2.85	C/F	1-309	[»]
3FGA	X-ray	2.70	C	1-309	[»]
3K7V	X-ray	2.85	C	1-309	[»]
3K7W	X-ray	2.96	C	1-309	[»]
3P71	X-ray	2.70	C	1-309	[»]

ProteinModelPortal

P67775.

SMR

P67775. Positions 6-293.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29395N.

IntAct

P67775. 72 interactions.

MINT

MINT-215645.

STRING

P67775.

PTM databases

PhosphoSite

P67775.

Polymorphism databases

DMDM

54038809.

Proteomic databases

PRIDE

P67775.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000481195; ENSP00000418447; ENSG00000113575.

GeneID

5515.

KEGG

hsa:5515.

UCSC

uc003kze.1. human.

Organism-specific databases

CTD

5515.

GeneCards

GC05M133530.

HGNC

HGNC:9299. PPP2CA.

HPA

CAB003848.

MIM

176915. gene.

neXtProt

NX_P67775.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG17795.

HOGENOM

HBG716770.

HOVERGEN

HBG000216.

InParanoid

P67775.

OMA

AIMEIDE.

OrthoDB

EOG4Q58PR.

PhylomeDB

P67775.

Enzyme and pathway databases

BioCyc

MetaCyc:HS03696-MONOMER.

Pathway_Interaction_DB

tgfbrpathway. TGF-beta receptor signaling.

Reactome

REACT_111102. Signal Transduction.
REACT_111217. Metabolism.
REACT_152. Cell Cycle, Mitotic.
REACT_383. DNA Replication.
REACT_474. Metabolism of carbohydrates.
REACT_604. Hemostasis.
REACT_6900. Immune System.

Gene expression databases

ArrayExpress

P67775.

Bgee

P67775.

CleanEx

HS_PPP2CA.

Genevestigator

P67775.

GermOnline

ENSG00000113575. Homo sapiens.

Family and domain databases

InterPro

IPR004843. Metallo_PEstase_dom.
IPR006186. Ser/Thr-sp_prot-phosphatase.
[Graphical view]

KO

K04382.

Pfam

PF00149. Metallophos. 1 hit.
[Graphical view]

PRINTS

PR00114. STPHPHTASE.

SMART

SM00156. PP2Ac. 1 hit.
[Graphical view]

PROSITE

PS00125. SER_THR_PHOSPHATASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00163. Vitamin E.

NextBio

21330.

SOURCE

Search...

Entry information

Entry name

PP2AA_HUMAN

Accession

Primary (citable) accession number: P67775
Secondary accession number(s): P05323, P13197

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 11, 2004
Last sequence update:	October 11, 2004
Last modified:	January 25, 2012
This is version 83 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.