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Protein

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

Gene

PPP3CA

Organism
Bos taurus (Bovine)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca2+-mediated signals (PubMed:15967565, PubMed:1715244, PubMed:1328240, PubMed:16411749). Many of the substrates contain a PxIxIT motif and/or a LxVP motif (By similarity). In response to increased Ca2+ levels, dephosphorylates and activates phosphatase SSH1 which results in cofilin dephosphorylation (By similarity). In response to increased Ca2+ levels following mitochondrial depolarization, dephosphorylates DNM1L inducing DNM1L translocation to the mitochondrion (By similarity). Dephosphorylates heat shock protein HSPB1 (PubMed:1328240). Dephosphorylates and activates transcription factor NFATC1 (By similarity). Dephosphorylates and inactivates transcription factor ELK1 (By similarity). Dephosphorylates DARPP32 (By similarity).By similarity4 Publications

Catalytic activityi

[a protein]-serine/threonine phosphate + H2O = [a protein]-serine/threonine + phosphate.4 Publications

Cofactori

Protein has several cofactor binding sites:

Enzyme regulationi

Activated by Ca2+-bound calmodulin following an increase in intracellular Ca2+ (PubMed:16411749). At low Ca2+ concentrations, the catalytic subunit (also known as calcineurin A) is inactive and is bound to the regulatory subunit (also known as calcineurin B) in which only two high-affinity binding sites are occupied by Ca2+ (By similarity). In response to elevated calcium levels, the occupancy of the low-affinity sites on calcineurin B by Ca2+ causes a conformational change of the C-terminal regulatory domain of calcineurin A, resulting in the exposure of the calmodulin-binding domain and in the partial activation of calcineurin A (PubMed:16411749). The subsequent binding of Ca2+-bound calmodulin leads to the displacement of the autoinhibitory domain from the active site and possibly of the autoinhibitory segment from the substrate binding site which fully activates calcineurin A (By similarity). Inhibited by immunosuppressant drug FK506 (tacrolimus) in complex with FKBP12 and also by immunosuppressant drug cyclosporin A (CsA) in complex with PPIA/cyclophilin A; the inhibition is Ca2+-dependent (PubMed:1715244).By similarity2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi90IronCombined sources1 Publication1
Metal bindingi92Iron; via tele nitrogenCombined sources1 Publication1
Metal bindingi118IronCombined sources1 Publication1
Metal bindingi118ZincCombined sources1 Publication1
Metal bindingi150ZincCombined sources1 Publication1
Active sitei151Proton donorBy similarity1
Metal bindingi199Zinc; via tele nitrogenCombined sources1 Publication1
Metal bindingi281Zinc; via tele nitrogenCombined sources1 Publication1

GO - Molecular functioni

  • calmodulin binding Source: UniProtKB
  • calmodulin-dependent protein phosphatase activity Source: UniProtKB
  • cyclosporin A binding Source: Ensembl
  • enzyme binding Source: Ensembl
  • metal ion binding Source: UniProtKB-KW
  • protein dimerization activity Source: Ensembl

GO - Biological processi

Keywordsi

Molecular functionCalmodulin-binding, Hydrolase, Protein phosphatase
LigandIron, Metal-binding, Zinc

Enzyme and pathway databases

BRENDAi3.1.3.16 908
ReactomeiR-BTA-2871809 FCERI mediated Ca+2 mobilization
R-BTA-4086398 Ca2+ pathway
R-BTA-5607763 CLEC7A (Dectin-1) induces NFAT activation

Names & Taxonomyi

Protein namesi
Recommended name:
Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform (EC:3.1.3.164 Publications)
Alternative name(s):
CAM-PRP catalytic subunit
Calmodulin-dependent calcineurin A subunit alpha isoform
Gene namesi
Name:PPP3CA
OrganismiBos taurus (Bovine)
Taxonomic identifieri9913 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos
Proteomesi
  • UP000009136 Componenti: Chromosome 6

Organism-specific databases

VGNCiVGNC:33265 PPP3CA

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cell projection, Cytoplasm, Membrane

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000588212 – 521Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoformAdd BLAST520

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineBy similarity1
Modified residuei224Nitrated tyrosineBy similarity1
Modified residuei469PhosphoserineBy similarity1
Modified residuei492PhosphoserineBy similarity1

Keywords - PTMi

Acetylation, Nitration, Phosphoprotein

Proteomic databases

PaxDbiP48452
PRIDEiP48452

PTM databases

iPTMnetiP48452

Expressioni

Tissue specificityi

Expressed in brain and thymus (at protein level) (PubMed:1715244, PubMed:1328240). Isoform 1: Expressed in brain. Isoform 2: Expressed in cardiac muscle.3 Publications

Gene expression databases

BgeeiENSBTAG00000016005

Interactioni

Subunit structurei

Forms a complex composed of a calmodulin-dependent catalytic subunit (also known as calcineurin A) and a regulatory Ca2+-binding subunit (also known as calcineurin B) (PubMed:7543369, PubMed:1715244). There are three catalytic subunits, each encoded by a separate gene (PPP3CA, PPP3CB, and PPP3CC) and two regulatory subunits which are also encoded by separate genes (PPP3R1 and PPP3R2). In response to an increase in Ca2+ intracellular levels, forms a complex composed of PPP3CA/calcineurin A, calcineurin B and calmodulin (PubMed:1715244). Interacts (via calcineurin B binding domain) with regulatory subunit PPP3R1/calcineurin B (PubMed:7543369). Interacts (via calmodulin-binding domain) with CALM1/calmodulin; the interaction depends on calmodulin binding to Ca2+ (PubMed:1715244). Forms a complex composed of MYOZ2 and ACTN1 (By similarity). Within the complex interacts with MYOZ2 (By similarity). Interacts with MYOZ1 (By similarity). Interacts with MYOZ3 (By similarity).Interacts with CIB1; the interaction increases upon cardiomyocyte hypertrophy (By similarity). Interacts with CHP1 and CHP2 (By similarity). Interacts with CRTC2 (By similarity). Interacts with DNM1L; the interaction dephosphorylates DNM1L and promotes its translocation to mitochondria (By similarity). Interacts with CMYA5; this interaction represses calcineurin activity in muscle (By similarity). Interacts (constitutively active form) with SYNPO2 (By similarity). Interacts with scaffold protein AKAP5 (via IAIIIT motif); the interaction recruits PPP3CA to the plasma membrane following L-type Ca2+-channel activation (By similarity). Interacts with NFATC2 (By similarity). Interacts with RCAN3 (By similarity). Interacts with PPIA (By similarity).By similarity2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei352Interaction with PxVP motif in substrateBy similarity1

GO - Molecular functioni

  • calmodulin binding Source: UniProtKB
  • enzyme binding Source: Ensembl
  • protein dimerization activity Source: Ensembl

Protein-protein interaction databases

IntActiP48452, 1 interactor
MINTiP48452
STRINGi9913.ENSBTAP00000021305

Structurei

Secondary structure

1521
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi31 – 34Combined sources4
Helixi43 – 51Combined sources9
Helixi58 – 74Combined sources17
Beta strandi77 – 81Combined sources5
Beta strandi83 – 88Combined sources6
Helixi95 – 105Combined sources11
Turni108 – 110Combined sources3
Beta strandi113 – 115Combined sources3
Beta strandi120 – 123Combined sources4
Helixi126 – 139Combined sources14
Turni141 – 143Combined sources3
Beta strandi144 – 146Combined sources3
Helixi154 – 159Combined sources6
Helixi162 – 169Combined sources8
Helixi172 – 182Combined sources11
Beta strandi188 – 191Combined sources4
Turni192 – 194Combined sources3
Beta strandi195 – 197Combined sources3
Helixi209 – 213Combined sources5
Beta strandi218 – 220Combined sources3
Beta strandi223 – 225Combined sources3
Helixi226 – 232Combined sources7
Beta strandi239 – 241Combined sources3
Beta strandi247 – 250Combined sources4
Turni252 – 255Combined sources4
Beta strandi256 – 260Combined sources5
Helixi262 – 272Combined sources11
Beta strandi275 – 279Combined sources5
Beta strandi287 – 290Combined sources4
Beta strandi295 – 305Combined sources11
Helixi311 – 313Combined sources3
Beta strandi319 – 325Combined sources7
Beta strandi328 – 334Combined sources7
Helixi344 – 346Combined sources3
Helixi349 – 369Combined sources21
Helixi392 – 395Combined sources4
Helixi397 – 409Combined sources13

3D structure databases

ProteinModelPortaliP48452
SMRiP48452
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP48452

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni56 – 340CatalyticCuratedAdd BLAST285
Regioni327 – 336Interaction with PxIxIF motif in substrateBy similarity10
Regioni341 – 369Calcineurin B binding1 PublicationAdd BLAST29
Regioni392 – 406Calmodulin-binding1 PublicationAdd BLAST15
Regioni407 – 414Autoinhibitory segmentBy similarity8
Regioni465 – 487Auto-inhibitory domainBy similarityAdd BLAST23

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi307 – 311SAPNY motifBy similarity5

Domaini

The autoinhibitory domain prevents access to the catalytic site.By similarity
The autoinhibitory segment prevents access to the substrate binding site.By similarity
Possible isomerization of Pro-309 within the SAPNY motif triggers a conformation switch which affects the organization and thus accessibility of the active site and the substrate binding region (PxIxIF motif). The trans- to cis-transition may favor calcineurin A activation and substrate binding. The reverse cis- to trans-transition may be enhanced by peptidyl-prolyl isomerases such as PPIA.By similarity

Sequence similaritiesi

Belongs to the PPP phosphatase family. PP-2B subfamily.Curated

Phylogenomic databases

eggNOGiKOG0375 Eukaryota
COG0639 LUCA
GeneTreeiENSGT00530000063087
HOGENOMiHOG000172699
HOVERGENiHBG002819
InParanoidiP48452
KOiK04348
OMAiLWSLKIW
OrthoDBiEOG091G094R
TreeFamiTF105557

Family and domain databases

Gene3Di3.60.21.10, 1 hit
InterProiView protein in InterPro
IPR004843 Calcineurin-like_PHP_ApaH
IPR029052 Metallo-depent_PP-like
IPR006186 Ser/Thr-sp_prot-phosphatase
PfamiView protein in Pfam
PF00149 Metallophos, 1 hit
PRINTSiPR00114 STPHPHTASE
SMARTiView protein in SMART
SM00156 PP2Ac, 1 hit
PROSITEiView protein in PROSITE
PS00125 SER_THR_PHOSPHATASE, 1 hit

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

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

Isoform 1 (identifier: P48452-1) [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
MSEPKAIDPK LSTTDRVVKA VPFPPSHRLT AKEVFDNDGK PRVDILKAHL
60 70 80 90 100
MKEGRLEETV ALRIITEGAS ILRQEKNLLD IDAPVTVCGD IHGQFFDLMK
110 120 130 140 150
LFEVGGSPAN TRYLFLGDYV DRGYFSIECV LYLWALKILY PKTLFLLRGN
160 170 180 190 200
HECRHLTEYF TFKQECKIKY SERVYDACMD AFDCLPLAAL MNQQFLCVHG
210 220 230 240 250
GLSPEINTLD DIRKLDRFKE PPAYGPMCDI LWSDPLEDFG NEKTQEHFTH
260 270 280 290 300
NTVRGCSYFY SYPAVCEFLQ HNNLLSILRA HEAQDAGYRM YRKSQTTGFP
310 320 330 340 350
SLITIFSAPN YLDVYNNKAA VLKYENNVMN IRQFNCSPHP YWLPNFMDVF
360 370 380 390 400
TWSLPFVGEK VTEMLVNVLN ICSDDELGSE EDGFDGATAA ARKEVIRNKI
410 420 430 440 450
RAIGKMARVF SVLREESESV LTLKGLTPTG MLPSGVLSGG KQTLQSATVE
460 470 480 490 500
AIEADEAIKG FSPQHKITSF EEAKGLDRIN ERMPPRRDAM PSDANLNSIN
510 520
KALASETNGT DSNGSNSSNI Q
Length:521
Mass (Da):58,672
Last modified:February 1, 1996 - v1
Checksum:iF3F153F22AB56BDF
GO
Isoform 2 (identifier: P48452-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     448-457: Missing.

Show »
Length:511
Mass (Da):57,643
Checksum:iC383F9EF7B41D775
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti367N → D in ABB22788 (PubMed:15967565).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_018561448 – 457Missing in isoform 2. 1 Publication10

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U33868 mRNA Translation: AAC48473.1
DQ231569 mRNA Translation: ABB22788.1
BC123668 mRNA Translation: AAI23669.1
PIRiA56968
RefSeqiNP_777212.1, NM_174787.2 [P48452-1]
XP_005207750.1, XM_005207693.3 [P48452-2]
UniGeneiBt.3966

Genome annotation databases

EnsembliENSBTAT00000021305; ENSBTAP00000021305; ENSBTAG00000016005 [P48452-1]
ENSBTAT00000056385; ENSBTAP00000047848; ENSBTAG00000016005 [P48452-2]
GeneIDi286852
KEGGibta:286852

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiPP2BA_BOVIN
AccessioniPrimary (citable) accession number: P48452
Secondary accession number(s): Q08DM4, Q309F2
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: February 1, 1996
Last modified: July 18, 2018
This is version 159 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. SIMILARITY comments
    Index of protein domains and families

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