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Protein

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

Gene

Ppp3ca

Organism
Mus musculus (Mouse)
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:7791792, PubMed:26794871). 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 (By similarity). Dephosphorylates and activates transcription factor NFATC1 (By similarity). Dephosphorylates and inactivates transcription factor ELK1 (By similarity). Dephosphorylates DARPP32 (By similarity).By similarity2 Publications

Catalytic activityi

[a protein]-serine/threonine phosphate + H2O = [a protein]-serine/threonine + phosphate.2 Publications

Cofactori

Protein has several cofactor binding sites:
  • Fe3+1 PublicationNote: Binds 1 Fe3+ ion per subunit.1 Publication
  • Zn2+1 PublicationNote: Binds 1 zinc ion per subunit.1 Publication

Activity regulationi

Activated by Ca2+-bound calmodulin following an increase in intracellular Ca2+ (PubMed:26794871). 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+ (PubMed:26794871). 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:26794871). 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 (PubMed:26794871). 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 (By similarity).By similarity1 Publication

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 pros nitrogenCombined sources1 Publication1

GO - Molecular functioni

GO - Biological processi

Keywordsi

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

Enzyme and pathway databases

ReactomeiR-MMU-2025928 Calcineurin activates NFAT
R-MMU-2871809 FCERI mediated Ca+2 mobilization
R-MMU-4086398 Ca2+ pathway
R-MMU-5607763 CLEC7A (Dectin-1) induces NFAT activation

Names & Taxonomyi

Protein namesi
Recommended name:
Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform (EC:3.1.3.162 Publications)
Alternative name(s):
CAM-PRP catalytic subunit
Calmodulin-dependent calcineurin A subunit alpha isoform
Short name:
CNA alpha1 Publication
Gene namesi
Name:Ppp3ca
Synonyms:Calna
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 3

Organism-specific databases

MGIiMGI:107164 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

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi348 – 521Missing : Loss of catalytic activity. Loss of interaction with PPP3R1/calreticulin B and calmodulin. 1 PublicationAdd BLAST174
Mutagenesisi389 – 521Missing : Increases catalytic activity independently of calmodulin. Loss of interaction with calmodulin. Does not affect interaction with PPP3R1/calreticulin B. 1 PublicationAdd BLAST133
Mutagenesisi406 – 521Missing : Increases catalytic activity independently of calmodulin. Does not affect interaction with PPP3R1/calreticulin B and calmodulin. 1 PublicationAdd BLAST116
Mutagenesisi442 – 521Missing : Increases basal catalytic activity. Does not affect interaction with PPP3R1/calreticulin B and calmodulin. 1 PublicationAdd BLAST80
Mutagenesisi477D → N: Greatly reduces inhibition of calcineurin phosphatase activity. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000588232 – 521Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoformAdd BLAST520

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineBy similarity1
Modified residuei224Nitrated tyrosineCombined sources1
Modified residuei469PhosphoserineBy similarity1
Modified residuei492PhosphoserineCombined sources1

Keywords - PTMi

Acetylation, Nitration, Phosphoprotein

Proteomic databases

MaxQBiP63328
PaxDbiP63328
PeptideAtlasiP63328
PRIDEiP63328

PTM databases

iPTMnetiP63328
PhosphoSitePlusiP63328
SwissPalmiP63328

Expressioni

Gene expression databases

BgeeiENSMUSG00000028161 Expressed in 294 organ(s), highest expression level in caudate-putamen
ExpressionAtlasiP63328 baseline and differential
GenevisibleiP63328 MM

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:26794871). 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 (By similarity). Interacts (via calcineurin B binding domain) with regulatory subunit PPP3R1/calcineurin B (PubMed:26794871). Interacts (via calmodulin-binding domain) with calmodulin; the interaction depends on calmodulin binding to Ca2+ (By similarity). Forms a complex composed of MYOZ2 and ACTN1 (PubMed:11114196). Within the complex interacts with MYOZ2 (PubMed:11114196). Interacts with MYOZ1 (PubMed:11114196). Interacts with MYOZ3 (By similarity). Interacts with CIB1; the interaction increases upon cardiomyocyte hypertrophy (PubMed:20639889). 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 (PubMed:21427212). 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). Interacts with RCAN1 (PubMed:12809556).By similarity5 Publications

Sites

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

Binary interactionsi

WithEntry#Exp.IntActNotes
Crtc2Q3U1822EBI-397208,EBI-8018890

GO - Molecular functioni

Protein-protein interaction databases

BioGridi202344, 18 interactors
ComplexPortaliCPX-1010 Calcineurin-Calmodulin complex, alpha-R1 variant
CPX-1049 Calcineurin-Calmodulin complex, alpha-R2 variant
CPX-1115 Calcineurin-Calmodulin-AKAP5 complex, alpha-R2 variant
CPX-881 Calcineurin-Calmodulin-AKAP5 complex, alpha-R1 variant
DIPiDIP-31543N
IntActiP63328, 15 interactors
MINTiP63328
STRINGi10090.ENSMUSP00000053101

Structurei

Secondary structure

1521
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP63328
SMRiP63328
ModBaseiSearch...
MobiDBiSearch...

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 segment1 Publication8
Regioni465 – 487Autoinhibitory domain1 PublicationAdd BLAST23

Motif

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

Domaini

The autoinhibitory domain prevents access to the catalytic site.1 Publication
The autoinhibitory segment prevents access to the substrate binding site.1 Publication
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
InParanoidiP63328
KOiK04348
OMAiLWSLKIW
OrthoDBiEOG091G094R
PhylomeDBiP63328
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: P63328-1) [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
MKEGRLEESV 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 SYPAVCDFLQ 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):58,644
Last modified:October 11, 2004 - v1
Checksum:i16530C27DDBF1F05
GO
Isoform 2 (identifier: P63328-2) [UniParc]FASTAAdd to basket

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

Note: No experimental confirmation available.
Show »
Length:511
Mass (Da):57,615
Checksum:i01428D70D67450BD
GO

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_018563448 – 457Missing in isoform 2. 1 Publication10

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
J05479 mRNA Translation: AAA37359.1
AK146387 mRNA Translation: BAE27131.1
AK150393 mRNA Translation: BAE29521.1
J04134 mRNA Translation: AAA37432.1
S78668 mRNA Translation: AAB34675.1
CCDSiCCDS17860.1 [P63328-1]
CCDS80027.1 [P63328-2]
PIRiA42232 A31257
RefSeqiNP_001280551.1, NM_001293622.1 [P63328-2]
NP_032939.1, NM_008913.5 [P63328-1]
UniGeneiMm.331389
Mm.486983

Genome annotation databases

EnsembliENSMUST00000056758; ENSMUSP00000053101; ENSMUSG00000028161 [P63328-1]
ENSMUST00000070198; ENSMUSP00000071040; ENSMUSG00000028161 [P63328-2]
GeneIDi19055
KEGGimmu:19055
UCSCiuc008rmg.2 mouse [P63328-1]
uc008rmh.2 mouse [P63328-2]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
J05479 mRNA Translation: AAA37359.1
AK146387 mRNA Translation: BAE27131.1
AK150393 mRNA Translation: BAE29521.1
J04134 mRNA Translation: AAA37432.1
S78668 mRNA Translation: AAB34675.1
CCDSiCCDS17860.1 [P63328-1]
CCDS80027.1 [P63328-2]
PIRiA42232 A31257
RefSeqiNP_001280551.1, NM_001293622.1 [P63328-2]
NP_032939.1, NM_008913.5 [P63328-1]
UniGeneiMm.331389
Mm.486983

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4ORBX-ray3.11A1-521[»]
ProteinModelPortaliP63328
SMRiP63328
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi202344, 18 interactors
ComplexPortaliCPX-1010 Calcineurin-Calmodulin complex, alpha-R1 variant
CPX-1049 Calcineurin-Calmodulin complex, alpha-R2 variant
CPX-1115 Calcineurin-Calmodulin-AKAP5 complex, alpha-R2 variant
CPX-881 Calcineurin-Calmodulin-AKAP5 complex, alpha-R1 variant
DIPiDIP-31543N
IntActiP63328, 15 interactors
MINTiP63328
STRINGi10090.ENSMUSP00000053101

PTM databases

iPTMnetiP63328
PhosphoSitePlusiP63328
SwissPalmiP63328

Proteomic databases

MaxQBiP63328
PaxDbiP63328
PeptideAtlasiP63328
PRIDEiP63328

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000056758; ENSMUSP00000053101; ENSMUSG00000028161 [P63328-1]
ENSMUST00000070198; ENSMUSP00000071040; ENSMUSG00000028161 [P63328-2]
GeneIDi19055
KEGGimmu:19055
UCSCiuc008rmg.2 mouse [P63328-1]
uc008rmh.2 mouse [P63328-2]

Organism-specific databases

CTDi5530
MGIiMGI:107164 Ppp3ca

Phylogenomic databases

eggNOGiKOG0375 Eukaryota
COG0639 LUCA
GeneTreeiENSGT00530000063087
HOGENOMiHOG000172699
HOVERGENiHBG002819
InParanoidiP63328
KOiK04348
OMAiLWSLKIW
OrthoDBiEOG091G094R
PhylomeDBiP63328
TreeFamiTF105557

Enzyme and pathway databases

ReactomeiR-MMU-2025928 Calcineurin activates NFAT
R-MMU-2871809 FCERI mediated Ca+2 mobilization
R-MMU-4086398 Ca2+ pathway
R-MMU-5607763 CLEC7A (Dectin-1) induces NFAT activation

Miscellaneous databases

ChiTaRSiPpp3ca mouse
PROiPR:P63328
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000028161 Expressed in 294 organ(s), highest expression level in caudate-putamen
ExpressionAtlasiP63328 baseline and differential
GenevisibleiP63328 MM

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
ProtoNetiSearch...

Entry informationi

Entry nameiPP2BA_MOUSE
AccessioniPrimary (citable) accession number: P63328
Secondary accession number(s): P12816
, P20652, Q3UCU1, Q64135
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 11, 2004
Last sequence update: October 11, 2004
Last modified: November 7, 2018
This is version 154 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, Direct protein sequencing, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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Main funding by: National Institutes of Health

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