UniProt functional annotation for P48452



	UniProt functional annotation for P48452

UniProt code: P48452.

Organism: Bos taurus (Bovine).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae; Bovinae; Bos.

Function: Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-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 Ca(2+) levels, dephosphorylates and activates phosphatase SSH1 which results in cofilin dephosphorylation (By similarity). In response to increased Ca(2+) 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). May dephosphorylate CRTC2 at 'Ser-171' resulting in CRTC2 dissociation from 14-3-3 proteins (By similarity). {ECO:0000250|UniProtKB:Q08209, ECO:0000269|PubMed:1328240, ECO:0000269|PubMed:15967565, ECO:0000269|PubMed:16411749, ECO:0000269|PubMed:1715244}.

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:1328240, ECO:0000269|PubMed:15967565, ECO:0000269|PubMed:16411749, ECO:0000269|PubMed:1715244};

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:1328240, ECO:0000269|PubMed:15967565, ECO:0000269|PubMed:16411749, ECO:0000269|PubMed:1715244};

Cofactor: Name=Fe(3+); Xref=ChEBI:CHEBI:29034; Evidence={ECO:0000269|PubMed:7543369}; Note=Binds 1 Fe(3+) ion per subunit. {ECO:0000269|PubMed:7543369};

Cofactor: Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:7543369}; Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:7543369};

Activity regulation: Activated by Ca(2+)-bound calmodulin following an increase in intracellular Ca(2+) (PubMed:16411749). 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+) (By similarity). 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 (PubMed:16411749). 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 (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 Ca(2+)-dependent (PubMed:1715244). {ECO:0000250|UniProtKB:P16298, ECO:0000269|PubMed:16411749, ECO:0000269|PubMed:1715244}.

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) (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 Ca(2+) 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 Ca(2+) (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 CRTC1. 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 Ca(2+)-channel activation (By similarity). Interacts with NFATC2 (By similarity). Interacts with RCAN3 (By similarity). Interacts with PPIA (By similarity). Interacts with UNC119 (By similarity). {ECO:0000250|UniProtKB:P63328, ECO:0000250|UniProtKB:P63329, ECO:0000250|UniProtKB:Q08209, ECO:0000269|PubMed:1715244, ECO:0000269|PubMed:7543369}.

Subcellular location: Cytoplasm {ECO:0000250|UniProtKB:Q08209}. Cell membrane {ECO:0000250|UniProtKB:Q08209}; Peripheral membrane protein {ECO:0000250|UniProtKB:Q08209}. Cell membrane, sarcolemma {ECO:0000250|UniProtKB:P63329}. Cytoplasm, myofibril, sarcomere, Z line {ECO:0000250|UniProtKB:P63329}. Cell projection, dendritic spine {ECO:0000250|UniProtKB:Q08209}. Note=Colocalizes with ACTN1 and MYOZ2 at the Z line in heart and skeletal muscle (By similarity). Recruited to the cell membrane by scaffold protein AKAP5 following L-type Ca(2+)- channel activation (By similarity). {ECO:0000250|UniProtKB:P63329, ECO:0000250|UniProtKB:Q08209}.

Tissue specificity: Expressed in brain and thymus (at protein level) (PubMed:1715244, PubMed:1328240). Isoform 1: Expressed in brain. Isoform 2: Expressed in cardiac muscle. {ECO:0000269|PubMed:1328240, ECO:0000269|PubMed:15967565, ECO:0000269|PubMed:1715244}.

Domain: The autoinhibitory domain prevents access to the catalytic site. {ECO:0000250|UniProtKB:P63328}.

Domain: The autoinhibitory segment prevents access to the substrate binding site. {ECO:0000250|UniProtKB:P63328}.

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

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

Annotations taken from UniProtKB at the EBI.


Organism:		Bos taurus (Bovine).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae; Bovinae; Bos.



Function:		Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-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 Ca(2+) levels, dephosphorylates and activates phosphatase SSH1 which results in cofilin dephosphorylation (By similarity). In response to increased Ca(2+) 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). May dephosphorylate CRTC2 at 'Ser-171' resulting in CRTC2 dissociation from 14-3-3 proteins (By similarity). {ECO:0000250\|UniProtKB:Q08209, ECO:0000269\|PubMed:1328240, ECO:0000269\|PubMed:15967565, ECO:0000269\|PubMed:16411749, ECO:0000269\|PubMed:1715244}.


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:1328240, ECO:0000269\|PubMed:15967565, ECO:0000269\|PubMed:16411749, ECO:0000269\|PubMed:1715244};
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:1328240, ECO:0000269\|PubMed:15967565, ECO:0000269\|PubMed:16411749, ECO:0000269\|PubMed:1715244};
Cofactor:		Name=Fe(3+); Xref=ChEBI:CHEBI:29034; Evidence={ECO:0000269\|PubMed:7543369}; Note=Binds 1 Fe(3+) ion per subunit. {ECO:0000269\|PubMed:7543369};
Cofactor:		Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269\|PubMed:7543369}; Note=Binds 1 zinc ion per subunit. {ECO:0000269\|PubMed:7543369};
Activity regulation:		Activated by Ca(2+)-bound calmodulin following an increase in intracellular Ca(2+) (PubMed:16411749). 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+) (By similarity). 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 (PubMed:16411749). 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 (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 Ca(2+)-dependent (PubMed:1715244). {ECO:0000250\|UniProtKB:P16298, ECO:0000269\|PubMed:16411749, ECO:0000269\|PubMed:1715244}.
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) (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 Ca(2+) 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 Ca(2+) (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 CRTC1. 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 Ca(2+)-channel activation (By similarity). Interacts with NFATC2 (By similarity). Interacts with RCAN3 (By similarity). Interacts with PPIA (By similarity). Interacts with UNC119 (By similarity). {ECO:0000250\|UniProtKB:P63328, ECO:0000250\|UniProtKB:P63329, ECO:0000250\|UniProtKB:Q08209, ECO:0000269\|PubMed:1715244, ECO:0000269\|PubMed:7543369}.
Subcellular location:		Cytoplasm {ECO:0000250\|UniProtKB:Q08209}. Cell membrane {ECO:0000250\|UniProtKB:Q08209}; Peripheral membrane protein {ECO:0000250\|UniProtKB:Q08209}. Cell membrane, sarcolemma {ECO:0000250\|UniProtKB:P63329}. Cytoplasm, myofibril, sarcomere, Z line {ECO:0000250\|UniProtKB:P63329}. Cell projection, dendritic spine {ECO:0000250\|UniProtKB:Q08209}. Note=Colocalizes with ACTN1 and MYOZ2 at the Z line in heart and skeletal muscle (By similarity). Recruited to the cell membrane by scaffold protein AKAP5 following L-type Ca(2+)- channel activation (By similarity). {ECO:0000250\|UniProtKB:P63329, ECO:0000250\|UniProtKB:Q08209}.
Tissue specificity:		Expressed in brain and thymus (at protein level) (PubMed:1715244, PubMed:1328240). Isoform 1: Expressed in brain. Isoform 2: Expressed in cardiac muscle. {ECO:0000269\|PubMed:1328240, ECO:0000269\|PubMed:15967565, ECO:0000269\|PubMed:1715244}.
Domain:		The autoinhibitory domain prevents access to the catalytic site. {ECO:0000250\|UniProtKB:P63328}.
Domain:		The autoinhibitory segment prevents access to the substrate binding site. {ECO:0000250\|UniProtKB:P63328}.
Domain:		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. {ECO:0000250\|UniProtKB:Q08209}.
Similarity:		Belongs to the PPP phosphatase family. PP-2B subfamily. {ECO:0000305}.