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Protein

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

Gene

PPP3CB

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 (PubMed:19154138, PubMed:26794871). Dephosphorylates and activates transcription factor NFATC1 (PubMed:19154138). Dephosphorylates and inactivates transcription factor ELK1 (PubMed:19154138). Dephosphorylates DARPP32 (PubMed:19154138).2 Publications

Miscellaneous

Unlike for protein substrates, PPP3CB activity towards synthetic phosphatase substrate p-nitrophenyl phosphate (pNPP) is increased in presence of the immunosuppressant complex FKBP12-FK506.1 Publication

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

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.2 Publications

Kineticsi

  1. KM=0.69 µM for NFATC11 Publication
  2. KM=0.7 µM for DARPP321 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi99IronCombined sources1 Publication1
    Metal bindingi101Iron; via tele nitrogenCombined sources1 Publication1
    Metal bindingi127IronCombined sources1 Publication1
    Metal bindingi127ZincCombined sources1 Publication1
    Metal bindingi159ZincCombined sources1 Publication1
    Active sitei160Proton donorBy similarity1
    Metal bindingi208Zinc; via tele nitrogenCombined sources1 Publication1
    Metal bindingi290Zinc; via pros nitrogenCombined sources1 Publication1

    GO - Molecular functioni

    • calcium ion binding Source: UniProtKB
    • calmodulin binding Source: UniProtKB
    • calmodulin-dependent protein phosphatase activity Source: UniProtKB
    • drug binding Source: UniProtKB
    • enzyme binding Source: UniProtKB
    • protein dimerization activity Source: UniProtKB
    • protein phosphatase 2B binding Source: UniProtKB
    • protein serine/threonine phosphatase activity Source: UniProtKB

    GO - Biological processi

    • axon extension Source: UniProtKB
    • calcineurin-NFAT signaling cascade Source: UniProtKB
    • calcium ion regulated exocytosis Source: UniProtKB
    • cellular response to drug Source: UniProtKB
    • dephosphorylation Source: UniProtKB
    • Fc-epsilon receptor signaling pathway Source: Reactome
    • heart development Source: Ensembl
    • learning Source: UniProtKB
    • locomotion involved in locomotory behavior Source: Ensembl
    • lymphangiogenesis Source: Ensembl
    • memory Source: UniProtKB
    • negative regulation of T cell mediated cytotoxicity Source: Ensembl
    • positive regulation of insulin secretion involved in cellular response to glucose stimulus Source: UniProtKB
    • positive regulation of transcription, DNA-templated Source: UniProtKB
    • positive regulation of transcription by RNA polymerase II Source: BHF-UCL
    • protein dephosphorylation Source: UniProtKB
    • protein phosphorylation Source: UniProtKB
    • regulation of insulin secretion Source: UniProtKB
    • regulation of synaptic plasticity Source: UniProtKB
    • response to cytokine Source: Ensembl
    • signal transduction Source: UniProtKB
    • social behavior Source: UniProtKB
    • T cell activation Source: UniProtKB
    • T cell differentiation Source: Ensembl
    • T cell homeostasis Source: Ensembl
    • T cell proliferation Source: UniProtKB
    • Wnt signaling pathway, calcium modulating pathway Source: Reactome

    Keywordsi

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

    Enzyme and pathway databases

    ReactomeiR-HSA-180024 DARPP-32 events
    R-HSA-2025928 Calcineurin activates NFAT
    R-HSA-2871809 FCERI mediated Ca+2 mobilization
    R-HSA-4086398 Ca2+ pathway
    R-HSA-5607763 CLEC7A (Dectin-1) induces NFAT activation
    R-HSA-9010642 ROBO receptors bind AKAP5
    SIGNORiP16298

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (EC:3.1.3.162 Publications)
    Alternative name(s):
    CAM-PRP catalytic subunit
    Calmodulin-dependent calcineurin A subunit beta isoform
    Short name:
    CNA beta1 Publication
    Gene namesi
    Name:PPP3CB
    Synonyms:CALNA2, CALNB, CNA2
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 10

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000107758.15
    HGNCiHGNC:9315 PPP3CB
    MIMi114106 gene
    neXtProtiNX_P16298

    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

    Cytoplasm

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi2 – 21Missing : Increases catalytic efficiency towards NFATC1 and DARPP32 but not towards a peptide substrate. Does not affect cytoplasmic localization and activation by calmodulin. 1 PublicationAdd BLAST20
    Mutagenesisi352L → A: Severe loss of calmodulin-mediated activation. Probably prevents recognition of substrates. 1 Publication1
    Mutagenesisi353P → A: Reduction of basal catalytic activity in absence of calmodulin. 1 Publication1
    Mutagenesisi356M → A: Modest increase in catalytic activity in absence of calmodulin. 1 Publication1
    Mutagenesisi357 – 524Missing : Loss of catalytic activity. Loss of interaction with PPP3R1/calreticulin B and calmodulin. 1 PublicationAdd BLAST168
    Mutagenesisi361W → A: Severe reduction of basal catalytic activity in absence of calmodulin. Severe loss of calmodulin-mediated activation. Probably prevents recognition of substrates. 1 Publication1
    Mutagenesisi365F → A: Moderate loss of calmodulin-mediated activation. Probably prevents recognition of substrates. 1 Publication1
    Mutagenesisi398 – 524Missing : Increases catalytic activity independently of calmodulin. Loss of interaction with calmodulin. Does not affect interaction with PPP3R1/calreticulin B. 1 PublicationAdd BLAST127
    Mutagenesisi415 – 524Missing : Increases catalytic activity independently of calmodulin. Does not affect interaction with PPP3R1/calreticulin B and calmodulin. 1 PublicationAdd BLAST110
    Mutagenesisi417R → A: Modest increase in catalytic activity in absence of calmodulin. Does not affect interaction with calmodulin. 1 Publication1
    Mutagenesisi418V → A: Does not affect catalytic activity in absence of calmodulin. Does not affect interaction with calmodulin. 1 Publication1
    Mutagenesisi419F → A: Modest increase in catalytic activity in absence of calmodulin. Does not affect interaction with calmodulin. 1 Publication1
    Mutagenesisi420S → A: Does not affect catalytic activity in absence of calmodulin. Does not affect interaction with calmodulin. 1 Publication1
    Mutagenesisi421V → A: Modest increase in catalytic activity in absence of calmodulin. Does not affect interaction with calmodulin. 1 Publication1
    Mutagenesisi422L → A: Modest increase in catalytic activity in absence of calmodulin. Does not affect interaction with calmodulin. 1 Publication1
    Mutagenesisi423R → A: Modest increase in catalytic activity in absence of calmodulin. Does not affect interaction with calmodulin. 1 Publication1
    Mutagenesisi451 – 524Missing : Increases basal catalytic activity. Does not affect interaction with PPP3R1/calreticulin B and calmodulin. 1 PublicationAdd BLAST74

    Organism-specific databases

    DisGeNETi5532
    OpenTargetsiENSG00000107758
    PharmGKBiPA33679

    Chemistry databases

    ChEMBLiCHEMBL5278

    Polymorphism and mutation databases

    BioMutaiPPP3CB
    DMDMi60659599

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Initiator methionineiRemovedCombined sources
    ChainiPRO_00000588252 – 524Serine/threonine-protein phosphatase 2B catalytic subunit beta isoformAdd BLAST523

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei2N-acetylalanineCombined sources1
    Modified residuei478PhosphoserineBy similarity1

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    EPDiP16298
    MaxQBiP16298
    PaxDbiP16298
    PeptideAtlasiP16298
    PRIDEiP16298
    ProteomicsDBi53341
    53342 [P16298-2]
    53343 [P16298-3]
    53344 [P16298-4]

    PTM databases

    DEPODiP16298
    iPTMnetiP16298
    PhosphoSitePlusiP16298
    SwissPalmiP16298

    Expressioni

    Gene expression databases

    BgeeiENSG00000107758
    CleanExiHS_PPP3CB
    ExpressionAtlasiP16298 baseline and differential
    GenevisibleiP16298 HS

    Organism-specific databases

    HPAiHPA008233
    HPA008823

    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). 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 PPP3CB/calcineurin A, calcineurin B and calmodulin. Interacts (via calcineurin B binding domain) with regulatory subunit PPP3R1/calcineurin B. Interacts (via calmodulin-binding domain) with calmodulin; the interaction depends on calmodulin binding to Ca2+.1 Publication

    Binary interactionsi

    Show more details

    GO - Molecular functioni

    • calmodulin binding Source: UniProtKB
    • enzyme binding Source: UniProtKB
    • protein dimerization activity Source: UniProtKB
    • protein phosphatase 2B binding Source: UniProtKB

    Protein-protein interaction databases

    BioGridi111524, 50 interactors
    ComplexPortaliCPX-1002 Calcineurin-Calmodulin complex, beta-R2 variant
    CPX-1009 Calcineurin-Calmodulin complex, beta-R1 variant
    CPX-1116 Calcineurin-Calmodulin-AKAP5 complex, beta-R2 variant
    CPX-998 Calcineurin-Calmodulin-AKAP5 complex, beta-R1 variant
    CORUMiP16298
    DIPiDIP-52337N
    IntActiP16298, 15 interactors
    MINTiP16298
    STRINGi9606.ENSP00000378306

    Chemistry databases

    BindingDBiP16298

    Structurei

    Secondary structure

    1524
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Helixi21 – 23Combined sources3
    Helixi40 – 43Combined sources4
    Helixi52 – 60Combined sources9
    Helixi67 – 82Combined sources16
    Beta strandi86 – 90Combined sources5
    Beta strandi92 – 97Combined sources6
    Helixi104 – 114Combined sources11
    Turni117 – 119Combined sources3
    Beta strandi122 – 124Combined sources3
    Beta strandi129 – 132Combined sources4
    Helixi135 – 148Combined sources14
    Turni150 – 152Combined sources3
    Beta strandi153 – 155Combined sources3
    Helixi163 – 168Combined sources6
    Helixi171 – 178Combined sources8
    Helixi181 – 192Combined sources12
    Beta strandi196 – 200Combined sources5
    Turni201 – 203Combined sources3
    Beta strandi204 – 209Combined sources6
    Helixi218 – 222Combined sources5
    Beta strandi232 – 234Combined sources3
    Helixi235 – 241Combined sources7
    Turni246 – 249Combined sources4
    Beta strandi256 – 259Combined sources4
    Turni261 – 263Combined sources3
    Beta strandi264 – 269Combined sources6
    Helixi271 – 281Combined sources11
    Beta strandi284 – 288Combined sources5
    Beta strandi296 – 299Combined sources4
    Turni304 – 306Combined sources3
    Beta strandi308 – 315Combined sources8
    Helixi320 – 322Combined sources3
    Beta strandi328 – 334Combined sources7
    Beta strandi337 – 343Combined sources7
    Helixi353 – 355Combined sources3
    Helixi358 – 378Combined sources21
    Beta strandi381 – 383Combined sources3
    Turni384 – 386Combined sources3
    Helixi479 – 485Combined sources7
    Helixi488 – 490Combined sources3

    3D structure databases

    ProteinModelPortaliP16298
    SMRiP16298
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni65 – 356CatalyticCuratedAdd BLAST292
    Regioni357 – 379Calcineurin B binding1 PublicationAdd BLAST23
    Regioni401 – 415Calmodulin-binding1 PublicationAdd BLAST15
    Regioni416 – 423Autoinhibitory segment1 Publication8
    Regioni474 – 496Autoinhibitory domain1 PublicationAdd BLAST23

    Motif

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Motifi316 – 320SAPNY motifBy similarity5

    Compositional bias

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Compositional biasi11 – 21Poly-ProSequence analysisAdd BLAST11

    Domaini

    The poly-Pro domain may confer substrate specificity.1 Publication
    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-318 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
    InParanoidiP16298
    KOiK04348
    OMAiQFDVKVG
    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 (4)i

    Sequence statusi: Complete.

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

    This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

    Note: Additional isoforms seem to exist. Calcineurin A beta isoform consists of at least two isoenzymes that may result from alternative splicing events.
    Isoform 1 (identifier: P16298-1) [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
    MAAPEPARAA PPPPPPPPPP PGADRVVKAV PFPPTHRLTS EEVFDLDGIP
    60 70 80 90 100
    RVDVLKNHLV KEGRVDEEIA LRIINEGAAI LRREKTMIEV EAPITVCGDI
    110 120 130 140 150
    HGQFFDLMKL FEVGGSPANT RYLFLGDYVD RGYFSIECVL YLWVLKILYP
    160 170 180 190 200
    STLFLLRGNH ECRHLTEYFT FKQECKIKYS ERVYEACMEA FDSLPLAALL
    210 220 230 240 250
    NQQFLCVHGG LSPEIHTLDD IRRLDRFKEP PAFGPMCDLL WSDPSEDFGN
    260 270 280 290 300
    EKSQEHFSHN TVRGCSYFYN YPAVCEFLQN NNLLSIIRAH EAQDAGYRMY
    310 320 330 340 350
    RKSQTTGFPS LITIFSAPNY LDVYNNKAAV LKYENNVMNI RQFNCSPHPY
    360 370 380 390 400
    WLPNFMDVFT WSLPFVGEKV TEMLVNVLSI CSDDELMTEG EDQFDGSAAA
    410 420 430 440 450
    RKEIIRNKIR AIGKMARVFS VLREESESVL TLKGLTPTGM LPSGVLAGGR
    460 470 480 490 500
    QTLQSATVEA IEAEKAIRGF SPPHRICSFE EAKGLDRINE RMPPRKDAVQ
    510 520
    QDGFNSLNTA HATENHGTGN HTAQ
    Length:524
    Mass (Da):59,024
    Last modified:February 1, 2005 - v2
    Checksum:i7661183F3C2362C8
    GO
    Isoform 2 (identifier: P16298-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         137-137: E → EHVLGTEDISINPHNNINE
         456-524: ATVEAIEAEK...NHGTGNHTAQ → GNDVMQLAVP...LLFFSSCLSS

    Show »
    Length:514
    Mass (Da):58,013
    Checksum:i1B0BFA63FB98E06D
    GO
    Isoform 3 (identifier: P16298-3) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         395-395: D → DV
         456-465: Missing.

    Show »
    Length:515
    Mass (Da):58,081
    Checksum:iA6762D9468A09B51
    GO
    Isoform 4 (identifier: P16298-4) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         395-395: D → DV

    Note: No experimental confirmation available.
    Show »
    Length:525
    Mass (Da):59,123
    Checksum:iADB0ECB75371B574
    GO

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_005096137E → EHVLGTEDISINPHNNINE in isoform 2. 1 Publication1
    Alternative sequenceiVSP_043803395D → DV in isoform 3 and isoform 4. 2 Publications1
    Alternative sequenceiVSP_005097456 – 524ATVEA…NHTAQ → GNDVMQLAVPQMDWGTPHSF ANNSHNACREFLLFFSSCLS S in isoform 2. 1 PublicationAdd BLAST69
    Alternative sequenceiVSP_012617456 – 465Missing in isoform 3. 1 Publication10

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    M29551 mRNA Translation: AAA35706.1
    M29550 mRNA Translation: AAA35705.1
    AJ488506 mRNA Translation: CAD32694.1
    AL353731 Genomic DNA No translation available.
    AL359074 Genomic DNA No translation available.
    CH471083 Genomic DNA Translation: EAW54497.1
    CH471083 Genomic DNA Translation: EAW54498.1
    BC028049 mRNA Translation: AAH28049.1
    CCDSiCCDS44436.1 [P16298-3]
    CCDS44437.1 [P16298-4]
    CCDS7328.1 [P16298-1]
    PIRiA36222
    B36222
    RefSeqiNP_001135825.1, NM_001142353.2 [P16298-4]
    NP_001135826.1, NM_001142354.2 [P16298-3]
    NP_001276897.1, NM_001289968.1 [P16298-2]
    NP_001276898.1, NM_001289969.1
    NP_066955.1, NM_021132.3 [P16298-1]
    UniGeneiHs.500067

    Genome annotation databases

    EnsembliENST00000360663; ENSP00000353881; ENSG00000107758 [P16298-1]
    ENST00000394828; ENSP00000378305; ENSG00000107758 [P16298-3]
    ENST00000394829; ENSP00000378306; ENSG00000107758 [P16298-4]
    GeneIDi5532
    KEGGihsa:5532
    UCSCiuc001jue.4 human [P16298-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Similar proteinsi

    Entry informationi

    Entry nameiPP2BB_HUMAN
    AccessioniPrimary (citable) accession number: P16298
    Secondary accession number(s): P16299
    , Q5F2F9, Q8N1F0, Q8N3W4
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 1, 1990
    Last sequence update: February 1, 2005
    Last modified: June 20, 2018
    This is version 155 of the entry and version 2 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

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 10
      Human chromosome 10: entries, gene names and cross-references to MIM
    2. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    3. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    4. SIMILARITY comments
      Index of protein domains and families

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