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Protein

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

Gene

PPP3CC

Organism
Homo sapiens (Human)
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. Dephosphorylates and activates transcription factor NFATC1. Dephosphorylates and inactivates transcription factor ELK1. Dephosphorylates DARPP32.1 Publication

Catalytic activityi

[a protein]-serine/threonine phosphate + H2O = [a protein]-serine/threonine + phosphate.1 Publication

Cofactori

Protein has several cofactor binding sites:
  • Fe3+By similarityNote: Binds 1 Fe3+ ion per subunit.By similarity
  • Zn2+By similarityNote: Binds 1 zinc ion per subunit.By similarity

Enzyme regulationi

Activated by Ca2+-bound calmodulin following an increase in intracellular Ca2+. 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+. 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. 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

Kineticsi

  1. KM=1.27 µM for NFATC11 Publication
  2. KM=0.94 µM for DARPP321 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi86IronBy similarity1
    Metal bindingi88Iron; via tele nitrogenBy similarity1
    Metal bindingi114IronBy similarity1
    Metal bindingi114ZincBy similarity1
    Metal bindingi146ZincBy similarity1
    Active sitei147Proton donorBy similarity1
    Metal bindingi195Zinc; via tele nitrogenBy similarity1
    Metal bindingi277Zinc; via pros nitrogenBy similarity1

    GO - Molecular functioni

    GO - Biological processi

    • brain development Source: Ensembl
    • calcineurin-NFAT signaling cascade Source: UniProtKB
    • positive regulation of synaptic vesicle endocytosis Source: Ensembl
    • protein dephosphorylation Source: UniProtKB

    Keywordsi

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

    Enzyme and pathway databases

    ReactomeiR-HSA-111447 Activation of BAD and translocation to mitochondria
    R-HSA-180024 DARPP-32 events
    SIGNORiP48454

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (EC:3.1.3.161 Publication)
    Alternative name(s):
    CAM-PRP catalytic subunit
    Calcineurin, testis-specific catalytic subunit
    Calmodulin-dependent calcineurin A subunit gamma isoform
    Gene namesi
    Name:PPP3CC
    Synonyms:CALNA3, CNA3
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 8

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000120910.14
    HGNCiHGNC:9316 PPP3CC
    MIMi114107 gene
    neXtProtiNX_P48454

    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

    Pathology & Biotechi

    Organism-specific databases

    DisGeNETi5533
    OpenTargetsiENSG00000120910
    PharmGKBiPA33680

    Polymorphism and mutation databases

    BioMutaiPPP3CC
    DMDMi257051041

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00000588281 – 512Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoformAdd BLAST512

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei483PhosphoserineCombined sources1

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    EPDiP48454
    MaxQBiP48454
    PaxDbiP48454
    PeptideAtlasiP48454
    PRIDEiP48454
    ProteomicsDBi55894
    55895 [P48454-2]

    PTM databases

    DEPODiP48454
    iPTMnetiP48454
    PhosphoSitePlusiP48454

    Expressioni

    Tissue specificityi

    Testis.1 Publication

    Gene expression databases

    BgeeiENSG00000120910
    CleanExiHS_PPP3CC
    ExpressionAtlasiP48454 baseline and differential
    GenevisibleiP48454 HS

    Organism-specific databases

    HPAiCAB024950
    HPA023396

    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:19154138). 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 PPP3CC/calcineurin A, calcineurin B and calmodulin (By similarity). Interacts (via calmodulin-binding domain) with calmodulin; the interaction depends on calmodulin binding to Ca2+ (By similarity).By similarity1 Publication

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    AMPHP494183EBI-2827192,EBI-7121510

    GO - Molecular functioni

    Protein-protein interaction databases

    BioGridi111525, 43 interactors
    ComplexPortaliCPX-1001 Calcineurin-Calmodulin complex, gamma-R1 variant
    CPX-1050 Calcineurin-Calmodulin complex, gamma-R2 variant
    CPX-1112 Calcineurin-Calmodulin-AKAP5 complex, gamma-R1 variant
    CPX-1113 Calcineurin-Calmodulin-AKAP5 complex, gamma-R1 variant
    CPX-1118 Calcineurin-Calmodulin-AKAP5 complex, gamma-R2 variant
    CPX-1119 Calcineurin-Calmodulin-AKAP5 complex, gamma-R2 variant
    IntActiP48454, 11 interactors
    STRINGi9606.ENSP00000240139

    Structurei

    3D structure databases

    ProteinModelPortaliP48454
    SMRiP48454
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni52 – 343CatalyticCuratedAdd BLAST292
    Regioni344 – 366Calcineurin B bindingBy similarityAdd BLAST23
    Regioni386 – 400Calmodulin-bindingBy similarityAdd BLAST15
    Regioni401 – 408Autoinhibitory segmentBy similarity8
    Regioni459 – 481Autoinhibitory domainBy similarityAdd BLAST23

    Motif

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Motifi303 – 307SAPNY 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-305 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
    InParanoidiP48454
    KOiK04348
    OMAiFSLQHKI
    OrthoDBiEOG091G094R
    PhylomeDBiP48454
    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 (3)i

    Sequence statusi: Complete.

    This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 1 (identifier: P48454-1) [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
    MSGRRFHLST TDRVIKAVPF PPTQRLTFKE VFENGKPKVD VLKNHLVKEG
    60 70 80 90 100
    RLEEEVALKI INDGAAILRQ EKTMIEVDAP ITVCGDIHGQ FFDLMKLFEV
    110 120 130 140 150
    GGSPSNTRYL FLGDYVDRGY FSIECVLYLW SLKINHPKTL FLLRGNHECR
    160 170 180 190 200
    HLTDYFTFKQ ECRIKYSEQV YDACMETFDC LPLAALLNQQ FLCVHGGMSP
    210 220 230 240 250
    EITSLDDIRK LDRFTEPPAF GPVCDLLWSD PSEDYGNEKT LEHYTHNTVR
    260 270 280 290 300
    GCSYFYSYPA VCEFLQNNNL LSIIRAHEAQ DAGYRMYRKS QATGFPSLIT
    310 320 330 340 350
    IFSAPNYLDV YNNKAAVLKY ENNVMNIRQF NCSPHPYWLP NFMDVFTWSL
    360 370 380 390 400
    PFVGEKVTEM LVNVLNICSD DELISDDEAE GSTTVRKEII RNKIRAIGKM
    410 420 430 440 450
    ARVFSILRQE SESVLTLKGL TPTGTLPLGV LSGGKQTIET ATVEAVEARE
    460 470 480 490 500
    AIRGFSLQHK IRSFEEARGL DRINERMPPR KDSIHAGGPM KSVTSAHSHA
    510
    AHRSDQGKKA HS
    Length:512
    Mass (Da):58,129
    Last modified:September 1, 2009 - v3
    Checksum:i1C3AA7996660D575
    GO
    Isoform 2 (identifier: P48454-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         442-451: Missing.

    Show »
    Length:502
    Mass (Da):57,073
    Checksum:i8ED89CC321A6DF0B
    GO
    Isoform 3 (identifier: P48454-3) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         380-380: E → EDHYIPSYQK

    Show »
    Length:521
    Mass (Da):59,262
    Checksum:iBC240A119202E701
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti485 – 486HA → YP in AAB23769 (PubMed:1339277).Curated2

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_061758501A → V. Corresponds to variant dbSNP:rs28764007Ensembl.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_045211380E → EDHYIPSYQK in isoform 3. 1 Publication1
    Alternative sequenceiVSP_037946442 – 451Missing in isoform 2. 2 Publications10

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    S46622 mRNA Translation: AAB23769.1
    AY007249 mRNA Translation: AAG02563.1
    AK299415 mRNA Translation: BAG61397.1
    AC037459 Genomic DNA No translation available.
    AC087854 Genomic DNA No translation available.
    CH471080 Genomic DNA Translation: EAW63677.1
    CH471080 Genomic DNA Translation: EAW63679.1
    BC004864 mRNA Translation: AAH04864.1
    CCDSiCCDS34859.1 [P48454-1]
    CCDS59093.1 [P48454-3]
    CCDS59094.1 [P48454-2]
    PIRiJC1283
    RefSeqiNP_001230903.1, NM_001243974.1 [P48454-3]
    NP_001230904.1, NM_001243975.1 [P48454-2]
    NP_005596.2, NM_005605.4 [P48454-1]
    UniGeneiHs.731683

    Genome annotation databases

    EnsembliENST00000240139; ENSP00000240139; ENSG00000120910 [P48454-1]
    ENST00000289963; ENSP00000289963; ENSG00000120910 [P48454-2]
    ENST00000397775; ENSP00000380878; ENSG00000120910 [P48454-3]
    GeneIDi5533
    KEGGihsa:5533
    UCSCiuc003xbs.4 human [P48454-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Entry informationi

    Entry nameiPP2BC_HUMAN
    AccessioniPrimary (citable) accession number: P48454
    Secondary accession number(s): B4DRT5, Q9BSS6, Q9H4M5
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
    Last sequence update: September 1, 2009
    Last modified: July 18, 2018
    This is version 164 of the entry and version 3 of the sequence. See 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

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. Human chromosome 8
      Human chromosome 8: 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. SIMILARITY comments
      Index of protein domains and families

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