PPP3R1 encodes calcineurin B type 1 (CnB1), the 19 kDa N-myristoylated EF-hand Ca2+-binding regulatory subunit of calcineurin (protein phosphatase 2B), the Ca2+/calmodulin-activated serine/threonine phosphatase. CnB binds constitutively to the CnB-binding helix of a calcineurin A catalytic subunit (PPP3CA, PPP3CB or PPP3CC) to form the obligate heterodimer; neither subunit is stable alone. CnB has no catalytic activity: its four EF hands bind Ca2+ (two high-affinity structural sites and two low-affinity regulatory sites), and Ca2+ occupancy of the low-affinity sites reorganises the CnA regulatory region, exposing the calmodulin-binding domain and allowing partial and then calmodulin-dependent full activation. CnB also forms part of the hydrophobic CnA/CnB groove that recognises LxVP docking motifs in substrates such as NFAT and is the binding site for the immunosuppressant complexes FKBP12-FK506 (tacrolimus) and cyclophilin A-cyclosporin A. Calcineurin is cytosolic, with pools tethered to the plasma membrane via CnB myristoylation and anchoring proteins such as AKAP79/150. Through dephosphorylation of NFAT transcription factors, calcineurin couples Ca2+ signals to gene expression in T cell activation downstream of the T cell receptor, in cardiac hypertrophy, and in neuronal and synaptic signaling. PPP3R1 is broadly expressed and highly abundant in brain.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004721 phosphoprotein phosphatase activity | IEA GO_REF:0000107 | MODIFY | Summary: IEA (Ensembl ortholog projection from rat Cnb1) assigning phosphoprotein phosphatase activity to calcineurin B. PPP3R1 is an EF-hand Ca2+-binding regulatory subunit with no phosphatase domain; catalysis is performed by the calcineurin A subunit. Reason: The catalytic activity belongs to CnA (PPP3CA/PPP3CB/PPP3CC); CnB is the obligate regulatory subunit that confers Ca2+ sensitivity and is required for activity. The appropriate MF for the subunit itself is calcium-dependent protein serine/threonine phosphatase regulator activity. Proposed replacements: calcium-dependent protein serine/threonine phosphatase regulator activity Supporting Evidence: PMID:23468591 CN is always composed of a catalytic A subunit (CNA), bound to a regulatory B subunit (CNB) that binds four Ca2+ ions PMID:26794871 a heterodimer composed of a catalytic subunit A and an essential regulatory subunit B PMID:11123943 Ca(2+) binding to the low-affinity sites of calcineurin B affects the conformation of calcineurin B and induces a conformational change of the regulatory domain of calcineurin A |
| GO:0004723 calcium-dependent protein serine/threonine phosphatase activity | NAS PMID:2558868 Isolation and sequence of a cDNA clone for human calcineurin... | MODIFY | Summary: NAS from the 1989 cDNA cloning paper of human calcineurin B. The paper describes CnB as the Ca2+-binding subunit of the phosphatase; it does not show catalytic activity of CnB. Reason: CnB has no catalytic domain; the activity is a property of the CnA-CnB holoenzyme with catalysis by CnA. Replace with the regulator activity that describes CnB's own contribution. Proposed replacements: calcium-dependent protein serine/threonine phosphatase regulator activity Supporting Evidence: PMID:2558868 We have identified and cloned human cDNA for the Ca2+-binding subunit of calcineurin PMID:23468591 CN is always composed of a catalytic A subunit (CNA), bound to a regulatory B subunit (CNB) that binds four Ca2+ ions PMID:26794871 a heterodimer composed of a catalytic subunit A and an essential regulatory subunit B |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: IEA from InterPro EF-hand domain. PPP3R1 has four EF-hand motifs that all bind Ca2+ (two high-affinity structural sites and two low-affinity regulatory sites). Reason: Ca2+ binding by CnB is well established structurally and biochemically and is the basis of its Ca2+-sensor/regulatory role. Supporting Evidence: PMID:23468591 CN is always composed of a catalytic A subunit (CNA), bound to a regulatory B subunit (CNB) that binds four Ca2+ ions PMID:11123943 Ca(2+) binding to the low-affinity sites of calcineurin B affects the conformation of calcineurin B and induces a conformational change of the regulatory domain of calcineurin A |
| GO:0005509 calcium ion binding | NAS PMID:2558868 Isolation and sequence of a cDNA clone for human calcineurin... | ACCEPT | Summary: NAS from the cloning paper describing CnB as the Ca2+-binding subunit of calcineurin. Reason: Correct; CnB binds four Ca2+ ions via EF hands. Supporting Evidence: PMID:2558868 We have identified and cloned human cDNA for the Ca2+-binding subunit of calcineurin PMID:27974827 constitutively bound to a regulatory CNB subunit that binds 4 Ca2+ ions |
| GO:0005515 protein binding | IPI PMID:12218175 Crystal structure of calcineurin-cyclophilin-cyclosporin sho... | MODIFY | Summary: IPI: crystal structure of calcineurin (CnA-CnB) with cyclophilin A-cyclosporin A (WITH PPIA, PPP3CA). The immunophilin-drug complex binds a composite surface of CnA and CnB. Reason: Generic protein binding is uninformative. The partner is a calcineurin A catalytic subunit, which CnB binds constitutively as its obligate regulatory subunit; the informative MF is phosphatase regulator activity (CnB Ca2+ occupancy drives the CnA conformational change required for activation). The cyclophilin contact is part of the drug-target interface rather than a physiological binding function of CnB, so no separate MF is proposed for it. Proposed replacements: calcium-dependent protein serine/threonine phosphatase regulator activity Supporting Evidence: PMID:12218175 The CyPA-CsA complex binds to a composite surface formed by the catalytic and regulatory subunits of CN PMID:11123943 Ca(2+) binding to the low-affinity sites of calcineurin B affects the conformation of calcineurin B and induces a conformational change of the regulatory domain of calcineurin A |
| GO:0005515 protein binding | IPI PMID:12357034 Crystal structure of human calcineurin complexed with cyclos... | MODIFY | Summary: IPI: crystal structure of human Cyp/CsA/calcineurin ternary complex (WITH PPIA, PPP3CA). Reason: Generic protein binding is uninformative. The partner is a calcineurin A catalytic subunit, which CnB binds constitutively as its obligate regulatory subunit; the informative MF is phosphatase regulator activity (CnB Ca2+ occupancy drives the CnA conformational change required for activation). The immunophilin-drug contact is the drug-binding interface at the CnA/CnB groove. Proposed replacements: calcium-dependent protein serine/threonine phosphatase regulator activity Supporting Evidence: PMID:12357034 We report the crystal structure of a Cyp/CsA/Cn ternary complex PMID:23468591 these drug-immunophilin complexes do not target the active site, but instead bind in a pocket ∼30 Å away at the interface of the CNA/CNB subunits PMID:11123943 Ca(2+) binding to the low-affinity sites of calcineurin B affects the conformation of calcineurin B and induces a conformational change of the regulatory domain of calcineurin A |
| GO:0005515 protein binding | IPI PMID:12809556 Phosphorylation of calcipressin 1 increases its ability to i... | REMOVE | Summary: IPI with RCAN1 (calcipressin 1), an endogenous calcineurin inhibitor. The study is about RCAN1 phosphorylation and calcineurin inhibition by the holoenzyme-binding RCAN1. Reason: Generic protein binding with a holoenzyme inhibitor; no informative MF for CnB itself can be derived (RCAN1 docks mainly on CnA PxIxIT/LxVP sites). The interaction is real but the annotation is uninformative. Supporting Evidence: PMID:12809556 Calcipressin 1 is an endogenous inhibitor of calcineurin |
| GO:0005515 protein binding | IPI PMID:16648474 Direct interaction and reciprocal regulation between ASK1 an... | REMOVE | Summary: IPI with ASK1 (MAP3K5), identified in a yeast two-hybrid screen with CnB as bait; ASK1 is a calcineurin substrate (dephosphorylated at Ser967). Reason: Enzyme-substrate interaction recorded as generic protein binding; uninformative for CnB's function. The relevant biology is captured by the holoenzyme's phosphatase activity on CnA. Supporting Evidence: PMID:16648474 calcineurin directly dephosphorylated ASK1 at serine 967 |
| GO:0005515 protein binding | IPI PMID:19896943 WITHDRAWN: USP14 stabilizes calcineurin and regulates NFAT/A... | REMOVE | Summary: IPI from a WITHDRAWN paper (USP14 as a calcineurin-binding protein). Reason: The supporting publication was withdrawn; the annotation should not stand, and generic protein binding is uninformative in any case. Supporting Evidence: PMID:19896943 This article has been withdrawn at the request of the author(s) and/or editor. |
| GO:0005515 protein binding | IPI PMID:22343722 Balanced interactions of calcineurin with AKAP79 regulate Ca... | MODIFY | Summary: IPI with PPP3CA isoform 1 from the AKAP79-calcineurin structural/cell biology study. Reason: Generic protein binding is uninformative. The partner is a calcineurin A catalytic subunit, which CnB binds constitutively as its obligate regulatory subunit; the informative MF is phosphatase regulator activity (CnB Ca2+ occupancy drives the CnA conformational change required for activation). Proposed replacements: calcium-dependent protein serine/threonine phosphatase regulator activity Supporting Evidence: PMID:22343722 A notable example is the A-kinase anchoring protein AKAP79, which juxtaposes the kinase PKA with the phosphatase calcineurin and other proteins, and targets them to a variety of locations in the plasma membrane PMID:11123943 Ca(2+) binding to the low-affinity sites of calcineurin B affects the conformation of calcineurin B and induces a conformational change of the regulatory domain of calcineurin A |
| GO:0005515 protein binding | IPI PMID:23468591 The molecular mechanism of substrate engagement and immunosu... | MODIFY | Summary: IPI with PPP3CA from the crystal structure of calcineurin bound to the viral inhibitor A238L. Reason: Generic protein binding is uninformative. The partner is a calcineurin A catalytic subunit, which CnB binds constitutively as its obligate regulatory subunit; the informative MF is phosphatase regulator activity (CnB Ca2+ occupancy drives the CnA conformational change required for activation). Proposed replacements: calcium-dependent protein serine/threonine phosphatase regulator activity Supporting Evidence: PMID:23468591 CN is always composed of a catalytic A subunit (CNA), bound to a regulatory B subunit (CNB) that binds four Ca2+ ions PMID:11123943 Ca(2+) binding to the low-affinity sites of calcineurin B affects the conformation of calcineurin B and induces a conformational change of the regulatory domain of calcineurin A |
| GO:0005515 protein binding | IPI PMID:24954618 The LxVP and PxIxIT NFAT motifs bind jointly to overlapping ... | MODIFY | Summary: IPI with PPP3CA from the NMR/structural study of NFAT LxVP and PxIxIT motifs binding calcineurin. Reason: Generic protein binding is uninformative. The partner is a calcineurin A catalytic subunit, which CnB binds constitutively as its obligate regulatory subunit; the informative MF is phosphatase regulator activity (CnB Ca2+ occupancy drives the CnA conformational change required for activation). Proposed replacements: calcium-dependent protein serine/threonine phosphatase regulator activity Supporting Evidence: PMID:24954618 CnB constitutively binds to the C-terminal side of CnA to form the heterodimer PMID:11123943 Ca(2+) binding to the low-affinity sites of calcineurin B affects the conformation of calcineurin B and induces a conformational change of the regulatory domain of calcineurin A |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IPI from a proteome-scale interaction screen (partner a calcineurin catalytic subunit or RCAN1). Reason: High-throughput interactome screen. The interaction detected is with a calcineurin catalytic subunit (PPP3CA or PPP3CC) or with RCAN1, i.e. the well-established CnA-CnB heterodimer or a holoenzyme inhibitor. Generic protein binding adds no functional information; the CnA-CnB association is captured by the calcineurin complex (GO:0005955) and phosphatase regulator activity (GO:0008597) annotations. |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | REMOVE | Summary: IPI from a proteome-scale interaction screen (partner a calcineurin catalytic subunit or RCAN1). Reason: High-throughput interactome screen. The interaction detected is with a calcineurin catalytic subunit (PPP3CA or PPP3CC) or with RCAN1, i.e. the well-established CnA-CnB heterodimer or a holoenzyme inhibitor. Generic protein binding adds no functional information; the CnA-CnB association is captured by the calcineurin complex (GO:0005955) and phosphatase regulator activity (GO:0008597) annotations. |
| GO:0005515 protein binding | IPI PMID:27880917 Phenotypic and Interaction Profiling of the Human Phosphatas... | REMOVE | Summary: IPI from a proteome-scale interaction screen (partner a calcineurin catalytic subunit or RCAN1). Reason: High-throughput interactome screen. The interaction detected is with a calcineurin catalytic subunit (PPP3CA or PPP3CC) or with RCAN1, i.e. the well-established CnA-CnB heterodimer or a holoenzyme inhibitor. Generic protein binding adds no functional information; the CnA-CnB association is captured by the calcineurin complex (GO:0005955) and phosphatase regulator activity (GO:0008597) annotations. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: IPI from a proteome-scale interaction screen (partner a calcineurin catalytic subunit or RCAN1). Reason: High-throughput interactome screen. The interaction detected is with a calcineurin catalytic subunit (PPP3CA or PPP3CC) or with RCAN1, i.e. the well-established CnA-CnB heterodimer or a holoenzyme inhibitor. Generic protein binding adds no functional information; the CnA-CnB association is captured by the calcineurin complex (GO:0005955) and phosphatase regulator activity (GO:0008597) annotations. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: IPI from a proteome-scale interaction screen (partner a calcineurin catalytic subunit or RCAN1). Reason: High-throughput interactome screen. The interaction detected is with a calcineurin catalytic subunit (PPP3CA or PPP3CC) or with RCAN1, i.e. the well-established CnA-CnB heterodimer or a holoenzyme inhibitor. Generic protein binding adds no functional information; the CnA-CnB association is captured by the calcineurin complex (GO:0005955) and phosphatase regulator activity (GO:0008597) annotations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI from a proteome-scale interaction screen (partner a calcineurin catalytic subunit or RCAN1). Reason: High-throughput interactome screen. The interaction detected is with a calcineurin catalytic subunit (PPP3CA or PPP3CC) or with RCAN1, i.e. the well-established CnA-CnB heterodimer or a holoenzyme inhibitor. Generic protein binding adds no functional information; the CnA-CnB association is captured by the calcineurin complex (GO:0005955) and phosphatase regulator activity (GO:0008597) annotations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI from a proteome-scale interaction screen (partner a calcineurin catalytic subunit or RCAN1). Reason: High-throughput interactome screen. The interaction detected is with a calcineurin catalytic subunit (PPP3CA or PPP3CC) or with RCAN1, i.e. the well-established CnA-CnB heterodimer or a holoenzyme inhibitor. Generic protein binding adds no functional information; the CnA-CnB association is captured by the calcineurin complex (GO:0005955) and phosphatase regulator activity (GO:0008597) annotations. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: IPI from a proteome-scale interaction screen (partner a calcineurin catalytic subunit or RCAN1). Reason: High-throughput interactome screen. The interaction detected is with a calcineurin catalytic subunit (PPP3CA or PPP3CC) or with RCAN1, i.e. the well-established CnA-CnB heterodimer or a holoenzyme inhibitor. Generic protein binding adds no functional information; the CnA-CnB association is captured by the calcineurin complex (GO:0005955) and phosphatase regulator activity (GO:0008597) annotations. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI from a proteome-scale interaction screen (partner a calcineurin catalytic subunit or RCAN1). Reason: High-throughput interactome screen. The interaction detected is with a calcineurin catalytic subunit (PPP3CA or PPP3CC) or with RCAN1, i.e. the well-established CnA-CnB heterodimer or a holoenzyme inhibitor. Generic protein binding adds no functional information; the CnA-CnB association is captured by the calcineurin complex (GO:0005955) and phosphatase regulator activity (GO:0008597) annotations. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI from a proteome-scale interaction screen (partner a calcineurin catalytic subunit or RCAN1). Reason: High-throughput interactome screen. The interaction detected is with a calcineurin catalytic subunit (PPP3CA or PPP3CC) or with RCAN1, i.e. the well-established CnA-CnB heterodimer or a holoenzyme inhibitor. Generic protein binding adds no functional information; the CnA-CnB association is captured by the calcineurin complex (GO:0005955) and phosphatase regulator activity (GO:0008597) annotations. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI from a proteome-scale interaction screen (partner a calcineurin catalytic subunit or RCAN1). Reason: High-throughput interactome screen. The interaction detected is with a calcineurin catalytic subunit (PPP3CA or PPP3CC) or with RCAN1, i.e. the well-established CnA-CnB heterodimer or a holoenzyme inhibitor. Generic protein binding adds no functional information; the CnA-CnB association is captured by the calcineurin complex (GO:0005955) and phosphatase regulator activity (GO:0008597) annotations. |
| GO:0005515 protein binding | IPI PMID:34446558 SPATA33 localizes calcineurin to the mitochondria and regula... | REMOVE | Summary: IPI with SPATA33, a sperm protein that binds calcineurin via a PxIxIT-type (PQIIIT) motif and localizes it to mitochondria. Reason: Generic protein binding; the PxIxIT docking groove is principally on CnA and the anchoring is a holoenzyme property. The finding is real but provides no informative MF for CnB. Supporting Evidence: PMID:34446558 SPATA33 interacts with PPP3CC via the PQIIIT sequence |
| GO:0005515 protein binding | IPI PMID:35914814 Chr21 protein-protein interactions: enrichment in proteins i... | REMOVE | Summary: IPI from a proteome-scale interaction screen (partner a calcineurin catalytic subunit or RCAN1). Reason: High-throughput interactome screen. The interaction detected is with a calcineurin catalytic subunit (PPP3CA or PPP3CC) or with RCAN1, i.e. the well-established CnA-CnB heterodimer or a holoenzyme inhibitor. Generic protein binding adds no functional information; the CnA-CnB association is captured by the calcineurin complex (GO:0005955) and phosphatase regulator activity (GO:0008597) annotations. |
| GO:0005515 protein binding | IPI PMID:37398436 AI-guided pipeline for protein-protein interaction drug disc... | REMOVE | Summary: IPI from a proteome-scale interaction screen (partner a calcineurin catalytic subunit or RCAN1). Reason: High-throughput interactome screen. The interaction detected is with a calcineurin catalytic subunit (PPP3CA or PPP3CC) or with RCAN1, i.e. the well-established CnA-CnB heterodimer or a holoenzyme inhibitor. Generic protein binding adds no functional information; the CnA-CnB association is captured by the calcineurin complex (GO:0005955) and phosphatase regulator activity (GO:0008597) annotations. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: IPI from a proteome-scale interaction screen (partner a calcineurin catalytic subunit or RCAN1). Reason: High-throughput interactome screen. The interaction detected is with a calcineurin catalytic subunit (PPP3CA or PPP3CC) or with RCAN1, i.e. the well-established CnA-CnB heterodimer or a holoenzyme inhibitor. Generic protein binding adds no functional information; the CnA-CnB association is captured by the calcineurin complex (GO:0005955) and phosphatase regulator activity (GO:0008597) annotations. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: IPI from a proteome-scale interaction screen (partner a calcineurin catalytic subunit or RCAN1). Reason: High-throughput interactome screen. The interaction detected is with a calcineurin catalytic subunit (PPP3CA or PPP3CC) or with RCAN1, i.e. the well-established CnA-CnB heterodimer or a holoenzyme inhibitor. Generic protein binding adds no functional information; the CnA-CnB association is captured by the calcineurin complex (GO:0005955) and phosphatase regulator activity (GO:0008597) annotations. |
| GO:0005515 protein binding | IPI PMID:8524402 Crystal structures of human calcineurin and the human FKBP12... | MODIFY | Summary: IPI with PPP3CA from the crystal structures of human calcineurin and the FKBP12-FK506-calcineurin complex. Reason: Generic protein binding is uninformative. The partner is a calcineurin A catalytic subunit, which CnB binds constitutively as its obligate regulatory subunit; the informative MF is phosphatase regulator activity (CnB Ca2+ occupancy drives the CnA conformational change required for activation). Proposed replacements: calcium-dependent protein serine/threonine phosphatase regulator activity Supporting Evidence: PMID:8524402 We report here the crystal structures of full-length human CaN at 2.1 A resolution PMID:11123943 Ca(2+) binding to the low-affinity sites of calcineurin B affects the conformation of calcineurin B and induces a conformational change of the regulatory domain of calcineurin A |
| GO:0005516 calmodulin binding | NAS PMID:2558868 Isolation and sequence of a cDNA clone for human calcineurin... | REMOVE | Summary: NAS from the cDNA cloning paper. Calmodulin binds the calmodulin-binding domain of calcineurin A, not CnB; CnB is itself calmodulin-like. Reason: No evidence that CnB binds calmodulin; the calmodulin-binding domain lies in CnA, and Ca2+-bound CnB acts to expose it for calmodulin binding. Supporting Evidence: PMID:11123943 Ca(2+) binding to the low-affinity sites of calcineurin B affects the conformation of calcineurin B and induces a conformational change of the regulatory domain of calcineurin A |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2730867 | KEEP AS NON CORE | Summary: TAS from Reactome modelling translocation of the dephosphorylated NFAT-calcineurin complex to the nucleus. Reason: Reactome models calcineurin co-translocating with NFAT; calcineurin's principal site of action is cytosolic/membrane-proximal. Retained as non-core location. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-4551465 | KEEP AS NON CORE | Summary: TAS from Reactome modelling translocation of the dephosphorylated NFAT-calcineurin complex to the nucleus. Reason: Reactome models calcineurin co-translocating with NFAT; calcineurin's principal site of action is cytosolic/membrane-proximal. Retained as non-core location. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular location (cytosol). Reason: CnB is a soluble cytosolic protein as part of calcineurin. |
| GO:0005829 cytosol | NAS PMID:22343722 Balanced interactions of calcineurin with AKAP79 regulate Ca... | ACCEPT | Summary: NAS from the AKAP79-calcineurin paper. Reason: Calcineurin is cytosolic with a pool anchored at membranes; consistent with the literature. Supporting Evidence: PMID:22343722 A notable example is the A-kinase anchoring protein AKAP79, which juxtaposes the kinase PKA with the phosphatase calcineurin and other proteins, and targets them to a variety of locations in the plasma membrane |
| GO:0005829 cytosol | NAS PMID:28126489 The protein serine/threonine phosphatases PP2A, PP1 and calc... | ACCEPT | Summary: NAS from a review of PP2A, PP1 and calcineurin in the neuronal cytoskeleton. Reason: Cytosolic location of calcineurin is well established. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-139906 | ACCEPT | Summary: TAS from Reactome calcineurin reactions (NFAT binding/dephosphorylation, BAD activation, calcineurin activation) located in the cytosol. Reason: Calcineurin acts on cytosolic substrates such as NFAT; correct location. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2025890 | ACCEPT | Summary: TAS from Reactome calcineurin reactions (NFAT binding/dephosphorylation, BAD activation, calcineurin activation) located in the cytosol. Reason: Calcineurin acts on cytosolic substrates such as NFAT; correct location. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730849 | ACCEPT | Summary: TAS from Reactome calcineurin reactions (NFAT binding/dephosphorylation, BAD activation, calcineurin activation) located in the cytosol. Reason: Calcineurin acts on cytosolic substrates such as NFAT; correct location. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730867 | ACCEPT | Summary: TAS from Reactome calcineurin reactions (NFAT binding/dephosphorylation, BAD activation, calcineurin activation) located in the cytosol. Reason: Calcineurin acts on cytosolic substrates such as NFAT; correct location. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730872 | ACCEPT | Summary: TAS from Reactome calcineurin reactions (NFAT binding/dephosphorylation, BAD activation, calcineurin activation) located in the cytosol. Reason: Calcineurin acts on cytosolic substrates such as NFAT; correct location. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-4551451 | ACCEPT | Summary: TAS from Reactome calcineurin reactions (NFAT binding/dephosphorylation, BAD activation, calcineurin activation) located in the cytosol. Reason: Calcineurin acts on cytosolic substrates such as NFAT; correct location. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-4551465 | ACCEPT | Summary: TAS from Reactome calcineurin reactions (NFAT binding/dephosphorylation, BAD activation, calcineurin activation) located in the cytosol. Reason: Calcineurin acts on cytosolic substrates such as NFAT; correct location. |
| GO:0005886 plasma membrane | EXP PMID:25255805 Global profiling of co- and post-translationally N-myristoyl... | ACCEPT | Summary: EXP from global profiling of N-myristoylated proteins in human cells; CnB is N-myristoylated at Gly2, providing a lipid anchor. Reason: CnB N-myristoylation supports membrane association, consistent with membrane tethering of calcineurin reported in other studies. Supporting Evidence: PMID:22343722 tethering of CNB to the cell membrane through its myristoyl modification PMID:20639889 Calcineurin can also associate with membrane phospholipids through its regulatory subunit CnB |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: IDA from Human Protein Atlas immunolocalization (plasma membrane). Reason: Consistent with myristoyl- and AKAP-dependent membrane localization of calcineurin. Supporting Evidence: PMID:22343722 tethering of CNB to the cell membrane through its myristoyl modification |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular location (cell membrane; lipid anchor). Reason: Supported by myristoylation and membrane tethering. Supporting Evidence: PMID:22343722 tethering of CNB to the cell membrane through its myristoyl modification |
| GO:0005955 calcineurin complex | IBA GO_REF:0000033 | ACCEPT | Summary: Calcineurin complex membership (IBA/IDA/IEA/NAS). PPP3R1 is the obligate regulatory B subunit of the calcineurin heterodimer. Reason: Core component annotation, supported by multiple crystal structures and biochemistry of the CnA-CnB heterodimer. Supporting Evidence: PMID:23468591 CN is always composed of a catalytic A subunit (CNA), bound to a regulatory B subunit (CNB) that binds four Ca2+ ions PMID:20639889 CnB is the exclusive and obligate binding partner of the CnA catalytic subunit, and neither protein is appreciably stable without expression of the other |
| GO:0005955 calcineurin complex | IDA PMID:12218175 Crystal structure of calcineurin-cyclophilin-cyclosporin sho... | ACCEPT | Summary: Calcineurin complex membership (IBA/IDA/IEA/NAS). PPP3R1 is the obligate regulatory B subunit of the calcineurin heterodimer. Reason: Core component annotation, supported by multiple crystal structures and biochemistry of the CnA-CnB heterodimer. Supporting Evidence: PMID:23468591 CN is always composed of a catalytic A subunit (CNA), bound to a regulatory B subunit (CNB) that binds four Ca2+ ions PMID:20639889 CnB is the exclusive and obligate binding partner of the CnA catalytic subunit, and neither protein is appreciably stable without expression of the other |
| GO:0005955 calcineurin complex | IDA PMID:12357034 Crystal structure of human calcineurin complexed with cyclos... | ACCEPT | Summary: Calcineurin complex membership (IBA/IDA/IEA/NAS). PPP3R1 is the obligate regulatory B subunit of the calcineurin heterodimer. Reason: Core component annotation, supported by multiple crystal structures and biochemistry of the CnA-CnB heterodimer. Supporting Evidence: PMID:23468591 CN is always composed of a catalytic A subunit (CNA), bound to a regulatory B subunit (CNB) that binds four Ca2+ ions PMID:20639889 CnB is the exclusive and obligate binding partner of the CnA catalytic subunit, and neither protein is appreciably stable without expression of the other |
| GO:0005955 calcineurin complex | IDA PMID:22343722 Balanced interactions of calcineurin with AKAP79 regulate Ca... | ACCEPT | Summary: Calcineurin complex membership (IBA/IDA/IEA/NAS). PPP3R1 is the obligate regulatory B subunit of the calcineurin heterodimer. Reason: Core component annotation, supported by multiple crystal structures and biochemistry of the CnA-CnB heterodimer. Supporting Evidence: PMID:23468591 CN is always composed of a catalytic A subunit (CNA), bound to a regulatory B subunit (CNB) that binds four Ca2+ ions PMID:20639889 CnB is the exclusive and obligate binding partner of the CnA catalytic subunit, and neither protein is appreciably stable without expression of the other |
| GO:0005955 calcineurin complex | IDA PMID:22688515 Na(+)/H(+) exchanger 1 directly binds to calcineurin A and a... | ACCEPT | Summary: Calcineurin complex membership (IBA/IDA/IEA/NAS). PPP3R1 is the obligate regulatory B subunit of the calcineurin heterodimer. Reason: Core component annotation, supported by multiple crystal structures and biochemistry of the CnA-CnB heterodimer. Supporting Evidence: PMID:23468591 CN is always composed of a catalytic A subunit (CNA), bound to a regulatory B subunit (CNB) that binds four Ca2+ ions PMID:20639889 CnB is the exclusive and obligate binding partner of the CnA catalytic subunit, and neither protein is appreciably stable without expression of the other |
| GO:0005955 calcineurin complex | IDA PMID:23468591 The molecular mechanism of substrate engagement and immunosu... | ACCEPT | Summary: Calcineurin complex membership (IBA/IDA/IEA/NAS). PPP3R1 is the obligate regulatory B subunit of the calcineurin heterodimer. Reason: Core component annotation, supported by multiple crystal structures and biochemistry of the CnA-CnB heterodimer. Supporting Evidence: PMID:23468591 CN is always composed of a catalytic A subunit (CNA), bound to a regulatory B subunit (CNB) that binds four Ca2+ ions PMID:20639889 CnB is the exclusive and obligate binding partner of the CnA catalytic subunit, and neither protein is appreciably stable without expression of the other |
| GO:0005955 calcineurin complex | IDA PMID:26794871 Cooperative autoinhibition and multi-level activation mechan... | ACCEPT | Summary: Calcineurin complex membership (IBA/IDA/IEA/NAS). PPP3R1 is the obligate regulatory B subunit of the calcineurin heterodimer. Reason: Core component annotation, supported by multiple crystal structures and biochemistry of the CnA-CnB heterodimer. Supporting Evidence: PMID:23468591 CN is always composed of a catalytic A subunit (CNA), bound to a regulatory B subunit (CNB) that binds four Ca2+ ions PMID:20639889 CnB is the exclusive and obligate binding partner of the CnA catalytic subunit, and neither protein is appreciably stable without expression of the other |
| GO:0005955 calcineurin complex | IDA PMID:27974827 Investigating the human Calcineurin Interaction Network usin... | ACCEPT | Summary: Calcineurin complex membership (IBA/IDA/IEA/NAS). PPP3R1 is the obligate regulatory B subunit of the calcineurin heterodimer. Reason: Core component annotation, supported by multiple crystal structures and biochemistry of the CnA-CnB heterodimer. Supporting Evidence: PMID:23468591 CN is always composed of a catalytic A subunit (CNA), bound to a regulatory B subunit (CNB) that binds four Ca2+ ions PMID:20639889 CnB is the exclusive and obligate binding partner of the CnA catalytic subunit, and neither protein is appreciably stable without expression of the other |
| GO:0005955 calcineurin complex | IEA GO_REF:0000107 | ACCEPT | Summary: Calcineurin complex membership (IBA/IDA/IEA/NAS). PPP3R1 is the obligate regulatory B subunit of the calcineurin heterodimer. Reason: Core component annotation, supported by multiple crystal structures and biochemistry of the CnA-CnB heterodimer. Supporting Evidence: PMID:23468591 CN is always composed of a catalytic A subunit (CNA), bound to a regulatory B subunit (CNB) that binds four Ca2+ ions PMID:20639889 CnB is the exclusive and obligate binding partner of the CnA catalytic subunit, and neither protein is appreciably stable without expression of the other |
| GO:0005955 calcineurin complex | NAS PMID:11123943 Low affinity Ca2+-binding sites of calcineurin B mediate con... | ACCEPT | Summary: Calcineurin complex membership (IBA/IDA/IEA/NAS). PPP3R1 is the obligate regulatory B subunit of the calcineurin heterodimer. Reason: Core component annotation, supported by multiple crystal structures and biochemistry of the CnA-CnB heterodimer. Supporting Evidence: PMID:23468591 CN is always composed of a catalytic A subunit (CNA), bound to a regulatory B subunit (CNB) that binds four Ca2+ ions PMID:20639889 CnB is the exclusive and obligate binding partner of the CnA catalytic subunit, and neither protein is appreciably stable without expression of the other |
| GO:0005955 calcineurin complex | NAS PMID:2558868 Isolation and sequence of a cDNA clone for human calcineurin... | ACCEPT | Summary: Calcineurin complex membership (IBA/IDA/IEA/NAS). PPP3R1 is the obligate regulatory B subunit of the calcineurin heterodimer. Reason: Core component annotation, supported by multiple crystal structures and biochemistry of the CnA-CnB heterodimer. Supporting Evidence: PMID:23468591 CN is always composed of a catalytic A subunit (CNA), bound to a regulatory B subunit (CNB) that binds four Ca2+ ions PMID:20639889 CnB is the exclusive and obligate binding partner of the CnA catalytic subunit, and neither protein is appreciably stable without expression of the other |
| GO:0008287 protein serine/threonine phosphatase complex | NAS PMID:22343722 Balanced interactions of calcineurin with AKAP79 regulate Ca... | ACCEPT | Summary: NAS, protein serine/threonine phosphatase complex (parent of calcineurin complex). Reason: Correct but less specific than calcineurin complex, which is also annotated. Supporting Evidence: PMID:23468591 CN is always composed of a catalytic A subunit (CNA), bound to a regulatory B subunit (CNB) that binds four Ca2+ ions |
| GO:0008597 calcium-dependent protein serine/threonine phosphatase regulator activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: calcium-dependent protein serine/threonine phosphatase regulator activity, propagated from the calcineurin B family node. Reason: This is the core MF of CnB: it binds CnA, confers Ca2+ sensitivity, and its Ca2+ occupancy induces the conformational change required for partial activation and for calmodulin-dependent full activation. Supporting Evidence: PMID:11123943 Ca(2+) binding to the low-affinity sites of calcineurin B affects the conformation of calcineurin B and induces a conformational change of the regulatory domain of calcineurin A PMID:11123943 This conformational change is needed for the partial activation of the enzyme in the absence of calmodulin and its full activation by calmodulin PMID:26794871 a heterodimer composed of a catalytic subunit A and an essential regulatory subunit B |
| GO:0019902 phosphatase binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phosphatase binding (IBA/IEA): CnB binds the calcineurin A catalytic subunit. Reason: Accurate description of the CnA-CnB interaction; the more informative MF is regulator activity (GO:0008597). This is intra-holoenzyme binding (CnB to the CnA catalytic subunit); it is retained because the partner is a distinct phosphatase polypeptide, unlike GO:0030346 protein phosphatase 2B binding, which would be self-referential for a calcineurin subunit and is not used here. Supporting Evidence: PMID:24954618 CnB constitutively binds to the C-terminal side of CnA to form the heterodimer |
| GO:0019902 phosphatase binding | IEA GO_REF:0000107 | ACCEPT | Summary: Phosphatase binding (IBA/IEA): CnB binds the calcineurin A catalytic subunit. Reason: Accurate description of the CnA-CnB interaction; the more informative MF is regulator activity (GO:0008597). This is intra-holoenzyme binding (CnB to the CnA catalytic subunit); it is retained because the partner is a distinct phosphatase polypeptide, unlike GO:0030346 protein phosphatase 2B binding, which would be self-referential for a calcineurin subunit and is not used here. Supporting Evidence: PMID:24954618 CnB constitutively binds to the C-terminal side of CnA to form the heterodimer |
| GO:0019902 phosphatase binding | IPI PMID:26794871 Cooperative autoinhibition and multi-level activation mechan... | ACCEPT | Summary: IPI phosphatase binding with PPP3CB, from the crystal structure of full-length calcineurin beta isoform. Reason: CnB binds CnA beta; well supported. This is intra-holoenzyme binding (CnB to the CnA catalytic subunit); it is retained because the partner is a distinct phosphatase polypeptide, unlike GO:0030346 protein phosphatase 2B binding, which would be self-referential for a calcineurin subunit and is not used here. Supporting Evidence: PMID:26794871 a heterodimer composed of a catalytic subunit A and an essential regulatory subunit B |
| GO:0019902 phosphatase binding | IPI PMID:27974827 Investigating the human Calcineurin Interaction Network usin... | ACCEPT | Summary: IPI phosphatase binding with PPP3CA from the structural study of the LxVP SLiM binding pocket at the CnA/CnB interface. Reason: CnB binds CnA; the LxVP substrate-docking pocket is formed jointly by CnA and CnB. This is intra-holoenzyme binding (CnB to the CnA catalytic subunit); it is retained because the partner is a distinct phosphatase polypeptide, unlike GO:0030346 protein phosphatase 2B binding, which would be self-referential for a calcineurin subunit and is not used here. Supporting Evidence: PMID:27974827 constitutively bound to a regulatory CNB subunit that binds 4 Ca2+ ions |
| GO:0019904 protein domain specific binding | IPI PMID:20639889 CIB1 is a regulator of pathological cardiac hypertrophy. | KEEP AS NON CORE | Summary: IPI protein domain specific binding with CIB1 (mouse cardiac study): the C-terminal EF-hand region of CIB1 binds CnB and recruits calcineurin to the sarcolemma. Reason: Reported interaction mediating context-specific (cardiomyocyte) membrane targeting; not central to CnB function. Supporting Evidence: PMID:20639889 the region corresponding to the functional C-terminal EF-hand domains of CIB1 is responsible for the interaction with CnB |
| GO:0033173 calcineurin-NFAT signaling cascade | IBA GO_REF:0000033 | ACCEPT | Summary: IBA calcineurin-NFAT signaling cascade. Reason: As an essential subunit of calcineurin, CnB is part of the enzyme that dephosphorylates NFAT; the Ca2+ signal is sensed partly through CnB. Supporting Evidence: PMID:8631904 the activation state of NFAT1 in T cells is remarkably sensitive to the level of calcineurin activity PMID:11123943 Ca(2+) binding to the low-affinity sites of calcineurin B affects the conformation of calcineurin B and induces a conformational change of the regulatory domain of calcineurin A |
| GO:0033173 calcineurin-NFAT signaling cascade | IDA PMID:22688515 Na(+)/H(+) exchanger 1 directly binds to calcineurin A and a... | ACCEPT | Summary: IDA from the NHE1-calcineurin study showing NHE1 binds CnA and promotes calcineurin/NFAT signaling. Reason: Calcineurin (CnA-CnB) is the effector of the cascade; consistent with the IBA. Supporting Evidence: PMID:22688515 The calcineurin A (CaNA) subunit was identified as a novel binding partner of plasma membrane Na(+)/H(+) exchanger 1 (NHE1) |
| GO:0042383 sarcolemma | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IEA (from rat ortholog) sarcolemma: CIB1-dependent translocation in hypertrophic cardiomyocytes. Reason: Context-specific location in cardiomyocytes. Supporting Evidence: PMID:20639889 Calcineurin can also associate with membrane phospholipids through its regulatory subunit CnB |
| GO:0045202 synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA synaptic location projected from rodent (SynGO-based) annotations. Reason: Calcineurin is abundant in neurons and acts at synapses (e.g. AKAP79/150-anchored pools), but synaptic location is a tissue context, not core. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:22688515 Na(+)/H(+) exchanger 1 directly binds to calcineurin A and a... | MARK AS OVER ANNOTATED | Summary: IDA positive regulation of transcription by RNA polymerase II, from NFAT reporter assays in the NHE1 study. Reason: Transcriptional effects are indirect, mediated by NFAT; the calcineurin-NFAT signaling cascade term already captures the relevant role. Supporting Evidence: PMID:22688515 The calcineurin A (CaNA) subunit was identified as a novel binding partner of plasma membrane Na(+)/H(+) exchanger 1 (NHE1) |
| GO:0070886 positive regulation of calcineurin-NFAT signaling cascade | NAS PMID:22343722 Balanced interactions of calcineurin with AKAP79 regulate Ca... | MODIFY | Summary: NAS positive regulation of calcineurin-NFAT signaling cascade. Reason: Calcineurin is the core effector of the calcineurin-NFAT cascade (it dephosphorylates NFAT), not a regulator of it; the cascade term itself is the accurate annotation. Proposed replacements: calcineurin-NFAT signaling cascade Supporting Evidence: PMID:22343722 A notable example is the A-kinase anchoring protein AKAP79, which juxtaposes the kinase PKA with the phosphatase calcineurin and other proteins, and targets them to a variety of locations in the plasma membrane |
| GO:0070886 positive regulation of calcineurin-NFAT signaling cascade | NAS PMID:8631904 Calcineurin binds the transcription factor NFAT1 and reversi... | MODIFY | Summary: NAS positive regulation of calcineurin-NFAT signaling cascade. Reason: Calcineurin is the core effector of the calcineurin-NFAT cascade (it dephosphorylates NFAT), not a regulator of it; the cascade term itself is the accurate annotation. Proposed replacements: calcineurin-NFAT signaling cascade Supporting Evidence: PMID:8631904 We also demonstrate a direct interaction between calcineurin and NFAT1 |
| GO:0098685 Schaffer collateral - CA1 synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA synaptic location projected from rodent (SynGO-based) annotations. Reason: Calcineurin is abundant in neurons and acts at synapses (e.g. AKAP79/150-anchored pools), but synaptic location is a tissue context, not core. |
| GO:0098686 hippocampal mossy fiber to CA3 synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA synaptic location projected from rodent (SynGO-based) annotations. Reason: Calcineurin is abundant in neurons and acts at synapses (e.g. AKAP79/150-anchored pools), but synaptic location is a tissue context, not core. |
| GO:0098688 parallel fiber to Purkinje cell synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA synaptic location projected from rodent (SynGO-based) annotations. Reason: Calcineurin is abundant in neurons and acts at synapses (e.g. AKAP79/150-anchored pools), but synaptic location is a tissue context, not core. |
| GO:0098693 regulation of synaptic vesicle cycle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA regulation of synaptic vesicle cycle (rodent projection). Reason: Neuronal calcineurin dephosphorylates presynaptic endocytic proteins; tissue-specific consequence of holoenzyme activity, non-core. |
| GO:0098794 postsynapse | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: IEA synaptic location projected from rodent (SynGO-based) annotations. Reason: Calcineurin is abundant in neurons and acts at synapses (e.g. AKAP79/150-anchored pools), but synaptic location is a tissue context, not core. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA synaptic location projected from rodent (SynGO-based) annotations. Reason: Calcineurin is abundant in neurons and acts at synapses (e.g. AKAP79/150-anchored pools), but synaptic location is a tissue context, not core. |
| GO:0099149 regulation of postsynaptic neurotransmitter receptor internalization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA regulation of postsynaptic neurotransmitter receptor internalization (rodent projection). Reason: Calcineurin is implicated in AMPA receptor endocytosis in LTD; neuronal context, non-core. |
| GO:0099170 postsynaptic modulation of chemical synaptic transmission | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA postsynaptic modulation of chemical synaptic transmission (rodent projection). Reason: Neuronal context of calcineurin activity; non-core. |
| GO:1905665 positive regulation of calcium ion import across plasma membrane | NAS PMID:17640527 AKAP79/150 anchoring of calcineurin controls neuronal L-type... | REMOVE | Summary: NAS positive regulation of calcium ion import across plasma membrane from the AKAP79/150-CaV1.2 study. Reason: In this study PKA enhances L-type channel activity and AKAP-anchored calcineurin opposes it; the positive effect is attributable to PKA, not calcineurin. Supporting Evidence: PMID:17640527 anchored CaN dominantly suppresses PKA enhancement of the channel |
| GO:1905949 negative regulation of calcium ion import across plasma membrane | NAS PMID:17640527 AKAP79/150 anchoring of calcineurin controls neuronal L-type... | KEEP AS NON CORE | Summary: NAS negative regulation of calcium ion import across plasma membrane from the AKAP79/150-CaV1.2 study. Reason: AKAP-anchored calcineurin suppresses PKA enhancement of neuronal L-type channels; real but context-specific holoenzyme effect. Supporting Evidence: PMID:17640527 anchored CaN dominantly suppresses PKA enhancement of the channel |
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Download this section (compressed HTML)Q: Should calcineurin B carry 'contributes_to calmodulin-dependent protein phosphatase activity' in GOA, given that CnA is inactive without CnB, rather than the current unqualified phosphatase activity rows inferred by ortholog projection and NAS?
Q: Does the LxVP-docking contribution of CnB residues (e.g. Val119, Leu123) warrant a distinct MF for substrate docking by the regulatory subunit, or is it adequately described by the holoenzyme activity?
Q: Do PPP3R1 and the testis-specific PPP3R2 differ in Ca2+ affinity or in which CnA isoforms they preferentially pair with in lymphocytes, and does this affect NFAT activation thresholds downstream of the TCR?
Experiment: Measure NFAT nuclear translocation and IL2 induction after TCR stimulation in human T cells expressing CnB EF-hand mutants that selectively abolish the low-affinity Ca2+ sites, to quantify how CnB Ca2+ sensing sets the threshold of the calcineurin-NFAT response.
Experiment: Compare membrane-proximal calcineurin signaling (AKAP79-anchored NFAT activation) in cells expressing wild-type CnB versus a non-myristoylatable G2A mutant, to test the contribution of CnB myristoylation to membrane targeting and signaling output.
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