UniProt functional annotation for P16298



	UniProt functional annotation for P16298

UniProt code: P16298.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-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). {ECO:0000269|PubMed:19154138, ECO:0000269|PubMed:26794871}.

Catalytic activity: Reaction=H2O + O-phospho-L-seryl-[protein] = L-seryl-[protein] + phosphate; Xref=Rhea:RHEA:20629, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:43474, ChEBI:CHEBI:83421; EC=3.1.3.16; Evidence={ECO:0000269|PubMed:19154138, ECO:0000269|PubMed:26794871};

Catalytic activity: Reaction=H2O + O-phospho-L-threonyl-[protein] = L-threonyl-[protein] + phosphate; Xref=Rhea:RHEA:47004, Rhea:RHEA-COMP:11060, Rhea:RHEA- COMP:11605, ChEBI:CHEBI:15377, ChEBI:CHEBI:30013, ChEBI:CHEBI:43474, ChEBI:CHEBI:61977; EC=3.1.3.16; Evidence={ECO:0000269|PubMed:19154138, ECO:0000269|PubMed:26794871};

Cofactor: Name=Fe(3+); Xref=ChEBI:CHEBI:29034; Evidence={ECO:0000269|PubMed:26794871}; Note=Binds 1 Fe(3+) ion per subunit. {ECO:0000269|PubMed:26794871};

Cofactor: Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:26794871}; Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:26794871};

Activity regulation: Activated by Ca(2+)-bound calmodulin following an increase in intracellular Ca(2+). At low Ca(2+) 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 Ca(2+). In response to elevated calcium levels, the occupancy of the low-affinity sites on calcineurin B by Ca(2+) 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 Ca(2+)-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. {ECO:0000269|PubMed:19154138, ECO:0000269|PubMed:26794871}.

Biophysicochemical properties: Kinetic parameters: KM=0.69 uM for NFATC1 {ECO:0000269|PubMed:19154138}; KM=0.7 uM for DARPP32 {ECO:0000269|PubMed:19154138};

Subunit: Forms a complex composed of a calmodulin-dependent catalytic subunit (also known as calcineurin A) and a regulatory Ca(2+)-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 Ca(2+) 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 Ca(2+). Interacts with SLC12A1 (By similarity). Interacts with SORL1 (By similarity). Interacts with UNC119 (By similarity). {ECO:0000250|UniProtKB:P20651, ECO:0000250|UniProtKB:P48453, ECO:0000269|PubMed:26794871}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:19154138}.

Domain: The poly-Pro domain may confer substrate specificity. {ECO:0000269|PubMed:19154138}.

Domain: The autoinhibitory domain prevents access to the catalytic site. {ECO:0000269|PubMed:26794871}.

Domain: The autoinhibitory segment prevents access to the substrate binding site. {ECO:0000269|PubMed:26794871}.

Domain: 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. {ECO:0000250|UniProtKB:Q08209}.

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. {ECO:0000269|PubMed:26794871}.

Similarity: Belongs to the PPP phosphatase family. PP-2B subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-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). {ECO:0000269\|PubMed:19154138, ECO:0000269\|PubMed:26794871}.


Catalytic activity:		Reaction=H2O + O-phospho-L-seryl-[protein] = L-seryl-[protein] + phosphate; Xref=Rhea:RHEA:20629, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:43474, ChEBI:CHEBI:83421; EC=3.1.3.16; Evidence={ECO:0000269\|PubMed:19154138, ECO:0000269\|PubMed:26794871};
Catalytic activity:		Reaction=H2O + O-phospho-L-threonyl-[protein] = L-threonyl-[protein] + phosphate; Xref=Rhea:RHEA:47004, Rhea:RHEA-COMP:11060, Rhea:RHEA- COMP:11605, ChEBI:CHEBI:15377, ChEBI:CHEBI:30013, ChEBI:CHEBI:43474, ChEBI:CHEBI:61977; EC=3.1.3.16; Evidence={ECO:0000269\|PubMed:19154138, ECO:0000269\|PubMed:26794871};
Cofactor:		Name=Fe(3+); Xref=ChEBI:CHEBI:29034; Evidence={ECO:0000269\|PubMed:26794871}; Note=Binds 1 Fe(3+) ion per subunit. {ECO:0000269\|PubMed:26794871};
Cofactor:		Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269\|PubMed:26794871}; Note=Binds 1 zinc ion per subunit. {ECO:0000269\|PubMed:26794871};
Activity regulation:		Activated by Ca(2+)-bound calmodulin following an increase in intracellular Ca(2+). At low Ca(2+) 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 Ca(2+). In response to elevated calcium levels, the occupancy of the low-affinity sites on calcineurin B by Ca(2+) 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 Ca(2+)-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. {ECO:0000269\|PubMed:19154138, ECO:0000269\|PubMed:26794871}.
Biophysicochemical properties:		Kinetic parameters: KM=0.69 uM for NFATC1 {ECO:0000269\|PubMed:19154138}; KM=0.7 uM for DARPP32 {ECO:0000269\|PubMed:19154138};
Subunit:		Forms a complex composed of a calmodulin-dependent catalytic subunit (also known as calcineurin A) and a regulatory Ca(2+)-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 Ca(2+) 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 Ca(2+). Interacts with SLC12A1 (By similarity). Interacts with SORL1 (By similarity). Interacts with UNC119 (By similarity). {ECO:0000250\|UniProtKB:P20651, ECO:0000250\|UniProtKB:P48453, ECO:0000269\|PubMed:26794871}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:19154138}.
Domain:		The poly-Pro domain may confer substrate specificity. {ECO:0000269\|PubMed:19154138}.
Domain:		The autoinhibitory domain prevents access to the catalytic site. {ECO:0000269\|PubMed:26794871}.
Domain:		The autoinhibitory segment prevents access to the substrate binding site. {ECO:0000269\|PubMed:26794871}.
Domain:		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. {ECO:0000250\|UniProtKB:Q08209}.
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. {ECO:0000269\|PubMed:26794871}.
Similarity:		Belongs to the PPP phosphatase family. PP-2B subfamily. {ECO:0000305}.