PPP3CA encodes calcineurin A alpha (CnA-alpha), one of three catalytic subunits of calcineurin (protein phosphatase 2B, EC 3.1.3.16), a Ca2+/calmodulin-activated protein serine/threonine phosphatase of the PPP family with a Fe3+/Zn2+ binuclear metal active site. CnA-alpha forms an obligate heterodimer with the Ca2+-binding regulatory subunit calcineurin B (PPP3R1); Ca2+ binding to CnB and Ca2+/calmodulin binding to the CaM-binding domain in the CnA regulatory region displace the C-terminal autoinhibitory domain from the active site. Substrates and regulators dock through PxIxIT motifs (pocket on CnA) and LxVP motifs (CnA/CnB interface), the latter being the site blocked by FKBP12-FK506 and cyclophilin-cyclosporin A. The best-known substrates are the NFATc transcription factors, whose dephosphorylation drives nuclear import and gene expression in T cell activation, cardiac hypertrophy, skeletal muscle fiber-type specification and neuronal plasticity; other direct substrates include Elk-1, DARPP-32, DNM1L (mitochondrial fission), SSH1L (cofilin activation), CRTCs, KLHL3 (renal WNK4/NCC regulation) and c-Myc. CnA-alpha is predominantly cytosolic and is anchored to specific sites by AKAP79/AKAP5 at the plasma membrane and dendritic spines and by calsarcins at the sarcomeric Z-disc. De novo PPP3CA variants cause neurodevelopmental disorders: catalytic-domain loss-of-function variants cause developmental and epileptic encephalopathy, and autoinhibitory-domain gain-of-function variants cause ACCIID syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Calcineurin A-alpha is cytoplasmic; the alpha, beta and gamma holoenzymes show the same cytoplasmic distribution. Reason: Cytoplasm/cytosol is the principal compartment in which calcineurin encounters NFAT and other substrates. Supporting Evidence: PMID:19154138 all CaN isoforms display the same cytoplasmic subcellular distribution |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Calcineurin is a soluble cytoplasmic phosphatase that dephosphorylates cytosolic NFAT and other substrates (e.g. DNM1L) in response to Ca2+ rises. Reason: Cytosol is the principal site of PPP3CA activity. Supporting Evidence: PMID:19154138 all CaN isoforms display the same cytoplasmic subcellular distribution PMID:18838687 Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria |
| GO:0005955 calcineurin complex | IBA GO_REF:0000033 | ACCEPT | Summary: PPP3CA is the catalytic A subunit of the calcineurin heterodimer (CnA/CnB, with PPP3R1); crystal structures of human calcineurin show the catalytic and regulatory subunits forming the composite surface recognized by immunophilin-drug complexes. Reason: Complex membership is structurally established and defines PPP3CA activity. Core cellular component, consistent with the PPP3CB and PPP3R1 reviews (GO:0005955). Supporting Evidence: PMID:8524402 In the native CaN structure, an auto-inhibitory element binds at the Zn/Fe-containing active site. PMID:12218175 The CyPA-CsA complex binds to a composite surface formed by the catalytic and regulatory subunits of CN PMID:12357034 We report the crystal structure of a Cyp/CsA/Cn ternary complex |
| GO:0033192 calmodulin-dependent protein phosphatase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PPP3CA is the catalytic A-alpha subunit of calcineurin, a Ca2+/calmodulin-dependent protein serine/threonine phosphatase. Recombinant holoenzymes containing CnA-alpha dephosphorylate NFAT, Elk-1, DARPP-32 and RII peptide, and Ca2+/calmodulin binding to the CaM-binding domain displaces the autoinhibitory domain to activate the enzyme. Reason: Most specific and accurate MF for PPP3CA; consistent with direct kinetic assays on the alpha holoenzyme and with the structural activation mechanism. Core function. Supporting Evidence: PMID:19154138 all human CaN holoenzymes containing either the alpha, beta, or gamma isoform of the catalytic subunit (CaN alpha, beta, or gamma, respectively) were expressed for the first time PMID:19154138 CaN alpha dephosphorylates the transcription factor Elk-1 with 7- and 2-fold higher catalytic efficiencies than the beta and gamma isoforms, respectively PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. PMID:23468591 Calcineurin (CN) is a conserved Ca(2+)/calmodulin-dependent ser/thr phosphatase and the target of immunosuppressants, FK506 and cyclosporin A (CSA) |
| GO:0005516 calmodulin binding | IBA GO_REF:0000033 | ACCEPT | Summary: PPP3CA binds Ca2+/calmodulin through the calmodulin-binding domain in its regulatory region; crystal structures of calmodulin with the CnA CaM-binding domain peptide and biophysical work on the regulatory domain show that this binding removes the autoinhibitory domain from the active site. Reason: Calmodulin binding is the activating input of calcineurin A and is directly shown with CnA peptides and the regulatory domain. Retained as a core MF that complements the catalytic activity. Supporting Evidence: PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. PMID:24191726 CaM binds CaN's regulatory domain (RD) and causes a conformational change that removes CaN's autoinhibitory domain (AID) from its catalytic site, activating CaN. |
| GO:0033173 calcineurin-NFAT signaling cascade | IBA GO_REF:0000033 | ACCEPT | Summary: PPP3CA dephosphorylates NFAT transcription factors (directly binding NFAT1 and NFATc1), enabling their nuclear translocation; this is the defining step of the calcineurin-NFAT signaling cascade. Reason: PPP3CA performs the enzymatic step that defines this pathway (GO:0033173 definition: NFAT activation as a consequence of dephosphorylation by Ca2+-activated calcineurin). Core process. Supporting Evidence: PMID:8631904 We also demonstrate a direct interaction between calcineurin and NFAT1 that is consistent with a direct enzyme-substrate relation between these two proteins PMID:23468591 One of the best-studied activities of CN is its dephosphorylation of the nuclear factor of activated T-cell family of transcription factors (NFATc1-c4), which allows NFAT to translocate to the nucleus where it induces the expression of genes required for T-cell activation PMID:27974827 Here we describe the crystal structure of CN in complex with its substrate NFATc1 |
| GO:0004722 protein serine/threonine phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Protein serine/threonine phosphatase activity is correct for PPP3CA (EC 3.1.3.16); direct dephosphorylation of serine/threonine sites in NFAT, Elk-1, KLHL3 Ser433 and SSH1L is documented. Reason: Correct parent of the more specific calmodulin-dependent protein phosphatase activity (GO:0033192); acceptable as stated. Supporting Evidence: PMID:19154138 CaN alpha dephosphorylates the transcription factor Elk-1 with 7- and 2-fold higher catalytic efficiencies than the beta and gamma isoforms, respectively PMID:30718414 We report herein that calcineurin normally dephosphorylates KLHL3S433-P and that this action is inhibited by CNIs |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Calcineurin A-alpha is cytoplasmic; the alpha, beta and gamma holoenzymes show the same cytoplasmic distribution. Reason: Cytoplasm/cytosol is the principal compartment in which calcineurin encounters NFAT and other substrates. Supporting Evidence: PMID:19154138 all CaN isoforms display the same cytoplasmic subcellular distribution |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: PPP3CA is recruited to the plasma membrane by anchoring proteins, notably AKAP79/AKAP5 (FRET/colocalization at the plasma membrane), and by PMCA4b; this pool controls local Ca2+-calcineurin-NFAT signaling. Reason: Experimentally supported but scaffold-dependent; a minor, context-specific pool relative to cytosol. Supporting Evidence: PMID:22343722 with wildtype AKAP79-CFP resulted in colocalization of the YFP-labeled proteins with AKAP79 at the plasma membrane, and in FRET between CFP and YFP |
| GO:0016787 hydrolase activity | IEA GO_REF:0000002 | MODIFY | Summary: Hydrolase activity (InterPro mapping) is correct but far too general for PPP3CA. Reason: Replace with the specific catalytic activity, calmodulin-dependent protein phosphatase activity (GO:0033192). Proposed replacements: calmodulin-dependent protein phosphatase activity Supporting Evidence: PMID:19154138 CaN alpha dephosphorylates the transcription factor Elk-1 with 7- and 2-fold higher catalytic efficiencies than the beta and gamma isoforms, respectively |
| GO:0030018 Z disc | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Calsarcins tether calcineurin to alpha-actinin at the Z-line of cardiac and skeletal muscle. Reason: Correct muscle-specific localization via calsarcin anchoring; not a universal location. Supporting Evidence: PMID:11114196 calsarcins, which tether calcineurin to alpha-actinin at the z-line of the sarcomere of cardiac and skeletal muscle cells |
| GO:0033173 calcineurin-NFAT signaling cascade | IEA GO_REF:0000117 | ACCEPT | Summary: PPP3CA dephosphorylates NFAT transcription factors (directly binding NFAT1 and NFATc1), enabling their nuclear translocation; this is the defining step of the calcineurin-NFAT signaling cascade. Reason: PPP3CA performs the enzymatic step that defines this pathway (GO:0033173 definition: NFAT activation as a consequence of dephosphorylation by Ca2+-activated calcineurin). Core process. Supporting Evidence: PMID:8631904 We also demonstrate a direct interaction between calcineurin and NFAT1 that is consistent with a direct enzyme-substrate relation between these two proteins PMID:23468591 One of the best-studied activities of CN is its dephosphorylation of the nuclear factor of activated T-cell family of transcription factors (NFATc1-c4), which allows NFAT to translocate to the nucleus where it induces the expression of genes required for T-cell activation PMID:27974827 Here we describe the crystal structure of CN in complex with its substrate NFATc1 |
| GO:0033192 calmodulin-dependent protein phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: PPP3CA is the catalytic A-alpha subunit of calcineurin, a Ca2+/calmodulin-dependent protein serine/threonine phosphatase. Recombinant holoenzymes containing CnA-alpha dephosphorylate NFAT, Elk-1, DARPP-32 and RII peptide, and Ca2+/calmodulin binding to the CaM-binding domain displaces the autoinhibitory domain to activate the enzyme. Reason: Most specific and accurate MF for PPP3CA; consistent with direct kinetic assays on the alpha holoenzyme and with the structural activation mechanism. Core function. Supporting Evidence: PMID:19154138 all human CaN holoenzymes containing either the alpha, beta, or gamma isoform of the catalytic subunit (CaN alpha, beta, or gamma, respectively) were expressed for the first time PMID:19154138 CaN alpha dephosphorylates the transcription factor Elk-1 with 7- and 2-fold higher catalytic efficiencies than the beta and gamma isoforms, respectively PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. PMID:23468591 Calcineurin (CN) is a conserved Ca(2+)/calmodulin-dependent ser/thr phosphatase and the target of immunosuppressants, FK506 and cyclosporin A (CSA) |
| GO:0042383 sarcolemma | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Sarcolemma localization (UniProt, by similarity to rat) is consistent with PMCA4b binding calcineurin A at the muscle plasma membrane. Reason: Muscle-specific membrane pool; non-core. Supporting Evidence: PMID:15955804 The interaction domains were located to the catalytic domain of PMCA4b and the catalytic domain of the calcineurin A subunit. |
| GO:0043197 dendritic spine | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: AKAP79/150 anchors calcineurin in dendritic spines of hippocampal neurons (FRAP shows AKAP-dependent immobilization of CN in spines). Reason: Neuron-specific localization; correct but not universal. Supporting Evidence: PMID:22343722 These results indicate that CN-AKAP binding contributes perceptibly to the immobilization of CN in dendritic spines |
| GO:0097720 calcineurin-mediated signaling | IEA GO_REF:0000002 | ACCEPT | Summary: Calcineurin-mediated signaling (parent of calcineurin-NFAT signaling cascade) is the Ca2+-triggered dephosphorylation of transcription factors by calcineurin, which PPP3CA catalyses. Reason: PPP3CA performs the defining enzymatic step. Correct, slightly broader than GO:0033173, and also covers non-NFAT calcineurin targets. Supporting Evidence: PMID:23468591 One of the best-studied activities of CN is its dephosphorylation of the nuclear factor of activated T-cell family of transcription factors (NFATc1-c4), which allows NFAT to translocate to the nucleus where it induces the expression of genes required for T-cell activation |
| GO:0005515 protein binding | IPI PMID:12577067 A proteomics strategy to elucidate functional protein-protei... | REMOVE | Summary: GRB2 interaction from a high-throughput EGF-signaling proteomics screen; no functional follow-up for calcineurin. Reason: Screen-only generic protein binding with no informative MF; removed per project rule for bare protein binding. |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | REMOVE | Summary: C16orf74/MICT1 yeast two-hybrid hit from a proteome-scale map. C16orf74 is a PxIxIT-motif calcineurin docking protein (see PMID:28881575). Reason: Generic protein binding of a docking partner; the informative activity belongs on the partner, not on PPP3CA. |
| GO:0005515 protein binding | IPI PMID:17474147 Systematic identification of SH3 domain-mediated human prote... | REMOVE | Summary: GRB2 SH3-domain peptide-array screen hit (the CnA N-terminal polyproline segment is a plausible SH3 ligand); no functional data. Reason: Screen-only generic protein binding; uninformative. |
| GO:0005515 protein binding | IPI PMID:19896943 WITHDRAWN: USP14 stabilizes calcineurin and regulates NFAT/A... | REMOVE | Summary: USP14 interaction reported in a paper that has been WITHDRAWN. Reason: Source publication is withdrawn; annotation should not be retained. 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:21900206 A directed protein interaction network for investigating int... | REMOVE | Summary: GRB2 interaction from a directed signaling interactome screen. Reason: Screen-only generic protein binding; uninformative. |
| GO:0005515 protein binding | IPI PMID:24418105 Direct association of the unique C-terminal tail of transmem... | REMOVE | Summary: The P/A-rich C-terminal tail of rodent TARP gamma-8 (Cacng8) binds calcineurin in a Ca2+/calmodulin-dependent manner, probably via the CnA hydrophobic PxIxIT-type pocket. Reason: Partner docking interaction (xeno, rodent partner); generic protein binding is uninformative. Supporting Evidence: PMID:24418105 These results indicate that the Ξ³-8 P/A-rich region is essential for binding calcineurin |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: PPP3R1 (CnB) two-hybrid interaction from HuRI. Reason: PPP3R1 binding is the calcineurin A/B heterodimer interaction already captured by part_of calcineurin complex (GO:0005955); generic protein binding adds no information. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: PPP3R1 (CnB) interaction from a neurodegenerative-disease interactome screen. Reason: PPP3R1 binding is the calcineurin A/B heterodimer interaction already captured by part_of calcineurin complex (GO:0005955); generic protein binding adds no information. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: PPP3R1 (CnB) interaction from a proteome-scale AP-MS network. Reason: PPP3R1 binding is the calcineurin A/B heterodimer interaction already captured by part_of calcineurin complex (GO:0005955); generic protein binding adds no information. |
| GO:0005515 protein binding | IPI PMID:37398436 AI-guided pipeline for protein-protein interaction drug disc... | REMOVE | Summary: PPP3R1 (CnB) interaction from an AI-guided PPI screen. Reason: PPP3R1 binding is the calcineurin A/B heterodimer interaction already captured by part_of calcineurin complex (GO:0005955); generic protein binding adds no information. |
| GO:0005515 protein binding | IPI PMID:8524402 Crystal structures of human calcineurin and the human FKBP12... | REMOVE | Summary: Crystal structure of the human CnA/CnB heterodimer (and with FKBP12-FK506). Reason: PPP3R1 binding is the calcineurin A/B heterodimer interaction already captured by part_of calcineurin complex (GO:0005955); generic protein binding adds no information. Supporting Evidence: PMID:8524402 In the native CaN structure, an auto-inhibitory element binds at the Zn/Fe-containing active site. |
| GO:0005829 cytosol | NAS PMID:22343722 Balanced interactions of calcineurin with AKAP79 regulate Ca... | ACCEPT | Summary: Calcineurin is a soluble cytoplasmic phosphatase that dephosphorylates cytosolic NFAT and other substrates (e.g. DNM1L) in response to Ca2+ rises. Reason: Cytosol is the principal site of PPP3CA activity. Supporting Evidence: PMID:22343722 only a rather narrow window of CN-AKAP79 affinities is compatible with normal NFAT signaling PMID:19154138 all CaN isoforms display the same cytoplasmic subcellular distribution PMID:18838687 Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria |
| GO:0005829 cytosol | NAS PMID:28126489 The protein serine/threonine phosphatases PP2A, PP1 and calc... | ACCEPT | Summary: Calcineurin is a soluble cytoplasmic phosphatase that dephosphorylates cytosolic NFAT and other substrates (e.g. DNM1L) in response to Ca2+ rises. Reason: Cytosol is the principal site of PPP3CA activity. Supporting Evidence: PMID:28126489 There is strong evidence that these enzymes interact with and dephosphorylate a variety of cytoskeletal proteins PMID:19154138 all CaN isoforms display the same cytoplasmic subcellular distribution PMID:18838687 Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria |
| GO:0070886 positive regulation of calcineurin-NFAT signaling cascade | NAS PMID:22343722 Balanced interactions of calcineurin with AKAP79 regulate Ca... | MODIFY | Summary: NAS assertion that PPP3CA positively regulates the calcineurin-NFAT signaling cascade. PPP3CA is the enzyme that executes this cascade (annotated as involved_in GO:0033173); it does not regulate it from outside. Reason: PPP3CA executes the cascade's core step rather than regulating it from outside, so the positive-regulation term is mis-framed; the correct term is the cascade itself (GO:0033173), as in the PPP3CB review. Proposed replacements: calcineurin-NFAT signaling cascade Supporting Evidence: PMID:22343722 only a rather narrow window of CN-AKAP79 affinities is compatible with normal NFAT signaling |
| GO:0070886 positive regulation of calcineurin-NFAT signaling cascade | NAS PMID:8631904 Calcineurin binds the transcription factor NFAT1 and reversi... | MODIFY | Summary: NAS assertion of positive regulation of the calcineurin-NFAT cascade. The paper shows calcineurin directly binds and dephosphorylates NFAT1, i.e. PPP3CA is the cascade's catalytic step rather than a regulator. Reason: The paper shows calcineurin is the cascade's catalytic step, so the positive-regulation term is mis-framed; the correct term is calcineurin-NFAT signaling cascade (GO:0033173), as in the PPP3CB review. Proposed replacements: calcineurin-NFAT signaling cascade Supporting Evidence: PMID:8631904 We also demonstrate a direct interaction between calcineurin and NFAT1 that is consistent with a direct enzyme-substrate relation between these two proteins |
| 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: AKAP79/150-anchored calcineurin dominantly suppresses PKA enhancement of L-type CaV1.2 current; the paper does not support calcineurin positively regulating Ca2+ import. Reason: Direction is contradicted by the cited study, in which PKA enhances the channel and anchored calcineurin opposes it; the negative-regulation row captures the reported effect. Removed, matching the PPP3R1 review of the same NAS row. 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: AKAP79/150-anchored calcineurin opposes PKA-mediated enhancement of neuronal L-type Ca2+ channel current. Reason: Consistent with the cited study (NAS); a neuronal, scaffold-dependent context rather than core function. Previously marked over-annotated together with the opposite-direction row; split here because only the positive row is contradicted. Supporting Evidence: PMID:17640527 anchored CaN dominantly suppresses PKA enhancement of the channel |
| GO:0004722 protein serine/threonine phosphatase activity | IMP PMID:30611118 Mitogenic Signals Stimulate the CREB Coactivator CRTC3 throu... | ACCEPT | Summary: Protein serine/threonine phosphatase activity is correct for PPP3CA (EC 3.1.3.16); direct dephosphorylation of serine/threonine sites in NFAT, Elk-1, KLHL3 Ser433 and SSH1L is documented. Reason: Correct parent of the more specific calmodulin-dependent protein phosphatase activity (GO:0033192); acceptable as stated. Supporting Evidence: PMID:30611118 CRTC1 and CRTC2 associate selectively with the calcium-dependent phosphatase calcineurin PMID:19154138 CaN alpha dephosphorylates the transcription factor Elk-1 with 7- and 2-fold higher catalytic efficiencies than the beta and gamma isoforms, respectively PMID:30718414 We report herein that calcineurin normally dephosphorylates KLHL3S433-P and that this action is inhibited by CNIs |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Calcineurin is a soluble cytoplasmic phosphatase that dephosphorylates cytosolic NFAT and other substrates (e.g. DNM1L) in response to Ca2+ rises. Reason: Cytosol is the principal site of PPP3CA activity. Supporting Evidence: PMID:19154138 all CaN isoforms display the same cytoplasmic subcellular distribution PMID:18838687 Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria |
| GO:1903235 positive regulation of calcium ion-dependent exocytosis of neurotransmitter | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from rat Ppp3ca for positive regulation of Ca2+-dependent neurotransmitter exocytosis (UniProt: positively regulates CACNA1B/CaV2.2-mediated release probability, by similarity). Reason: Neuronal synaptic context, acts_upstream_of_or_within; non-core. |
| GO:0033192 calmodulin-dependent protein phosphatase activity | IDA PMID:30718414 Calcineurin dephosphorylates Kelch-like 3, reversing phospho... | ACCEPT | Summary: PPP3CA is the catalytic A-alpha subunit of calcineurin, a Ca2+/calmodulin-dependent protein serine/threonine phosphatase. Recombinant holoenzymes containing CnA-alpha dephosphorylate NFAT, Elk-1, DARPP-32 and RII peptide, and Ca2+/calmodulin binding to the CaM-binding domain displaces the autoinhibitory domain to activate the enzyme. Reason: Most specific and accurate MF for PPP3CA; consistent with direct kinetic assays on the alpha holoenzyme and with the structural activation mechanism. Core function. Supporting Evidence: PMID:30718414 We report herein that calcineurin normally dephosphorylates KLHL3S433-P and that this action is inhibited by CNIs PMID:19154138 all human CaN holoenzymes containing either the alpha, beta, or gamma isoform of the catalytic subunit (CaN alpha, beta, or gamma, respectively) were expressed for the first time PMID:19154138 CaN alpha dephosphorylates the transcription factor Elk-1 with 7- and 2-fold higher catalytic efficiencies than the beta and gamma isoforms, respectively PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. PMID:23468591 Calcineurin (CN) is a conserved Ca(2+)/calmodulin-dependent ser/thr phosphatase and the target of immunosuppressants, FK506 and cyclosporin A (CSA) |
| GO:0110062 negative regulation of angiotensin-activated signaling pathway | IDA PMID:30718414 Calcineurin dephosphorylates Kelch-like 3, reversing phospho... | KEEP AS NON CORE | Summary: Calcineurin dephosphorylates KLHL3 Ser433, reversing angiotensin II/PKC phosphorylation and restoring KLHL3-mediated WNK4 degradation in distal convoluted tubule cells. Reason: Direct, well-supported renal context of PPP3CA catalysis; non-core because it is one of many substrate contexts. Supporting Evidence: PMID:30718414 We report herein that calcineurin normally dephosphorylates KLHL3S433-P and that this action is inhibited by CNIs |
| GO:0004722 protein serine/threonine phosphatase activity | IDA PMID:30718414 Calcineurin dephosphorylates Kelch-like 3, reversing phospho... | ACCEPT | Summary: Protein serine/threonine phosphatase activity is correct for PPP3CA (EC 3.1.3.16); direct dephosphorylation of serine/threonine sites in NFAT, Elk-1, KLHL3 Ser433 and SSH1L is documented. Reason: Correct parent of the more specific calmodulin-dependent protein phosphatase activity (GO:0033192); acceptable as stated. Supporting Evidence: PMID:30718414 We report herein that calcineurin normally dephosphorylates KLHL3S433-P and that this action is inhibited by CNIs PMID:19154138 CaN alpha dephosphorylates the transcription factor Elk-1 with 7- and 2-fold higher catalytic efficiencies than the beta and gamma isoforms, respectively |
| GO:0005516 calmodulin binding | EXP PMID:18384083 The complex structure of calmodulin bound to a calcineurin p... | ACCEPT | Summary: PPP3CA binds Ca2+/calmodulin through the calmodulin-binding domain in its regulatory region; crystal structures of calmodulin with the CnA CaM-binding domain peptide and biophysical work on the regulatory domain show that this binding removes the autoinhibitory domain from the active site. Reason: Calmodulin binding is the activating input of calcineurin A and is directly shown with CnA peptides and the regulatory domain. Retained as a core MF that complements the catalytic activity. Supporting Evidence: PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. PMID:24191726 CaM binds CaN's regulatory domain (RD) and causes a conformational change that removes CaN's autoinhibitory domain (AID) from its catalytic site, activating CaN. |
| GO:0005516 calmodulin binding | IDA PMID:18384083 The complex structure of calmodulin bound to a calcineurin p... | ACCEPT | Summary: PPP3CA binds Ca2+/calmodulin through the calmodulin-binding domain in its regulatory region; crystal structures of calmodulin with the CnA CaM-binding domain peptide and biophysical work on the regulatory domain show that this binding removes the autoinhibitory domain from the active site. Reason: Calmodulin binding is the activating input of calcineurin A and is directly shown with CnA peptides and the regulatory domain. Retained as a core MF that complements the catalytic activity. Supporting Evidence: PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. PMID:24191726 CaM binds CaN's regulatory domain (RD) and causes a conformational change that removes CaN's autoinhibitory domain (AID) from its catalytic site, activating CaN. |
| GO:0005516 calmodulin binding | IPI PMID:18384083 The complex structure of calmodulin bound to a calcineurin p... | ACCEPT | Summary: PPP3CA binds Ca2+/calmodulin through the calmodulin-binding domain in its regulatory region; crystal structures of calmodulin with the CnA CaM-binding domain peptide and biophysical work on the regulatory domain show that this binding removes the autoinhibitory domain from the active site. Reason: Calmodulin binding is the activating input of calcineurin A and is directly shown with CnA peptides and the regulatory domain. Retained as a core MF that complements the catalytic activity. Supporting Evidence: PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. PMID:24191726 CaM binds CaN's regulatory domain (RD) and causes a conformational change that removes CaN's autoinhibitory domain (AID) from its catalytic site, activating CaN. |
| GO:0005516 calmodulin binding | EXP PMID:24191726 The distal helix in the regulatory domain of calcineurin is ... | ACCEPT | Summary: PPP3CA binds Ca2+/calmodulin through the calmodulin-binding domain in its regulatory region; crystal structures of calmodulin with the CnA CaM-binding domain peptide and biophysical work on the regulatory domain show that this binding removes the autoinhibitory domain from the active site. Reason: Calmodulin binding is the activating input of calcineurin A and is directly shown with CnA peptides and the regulatory domain. Retained as a core MF that complements the catalytic activity. Supporting Evidence: PMID:24191726 CaM binds CaN's regulatory domain (RD) and causes a conformational change that removes CaN's autoinhibitory domain (AID) from its catalytic site, activating CaN. PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. |
| GO:0005516 calmodulin binding | IPI PMID:24191726 The distal helix in the regulatory domain of calcineurin is ... | ACCEPT | Summary: PPP3CA binds Ca2+/calmodulin through the calmodulin-binding domain in its regulatory region; crystal structures of calmodulin with the CnA CaM-binding domain peptide and biophysical work on the regulatory domain show that this binding removes the autoinhibitory domain from the active site. Reason: Calmodulin binding is the activating input of calcineurin A and is directly shown with CnA peptides and the regulatory domain. Retained as a core MF that complements the catalytic activity. Supporting Evidence: PMID:24191726 CaM binds CaN's regulatory domain (RD) and causes a conformational change that removes CaN's autoinhibitory domain (AID) from its catalytic site, activating CaN. PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. |
| GO:0005516 calmodulin binding | EXP PMID:27187005 Calcineurin in a Crowded World. | ACCEPT | Summary: PPP3CA binds Ca2+/calmodulin through the calmodulin-binding domain in its regulatory region; crystal structures of calmodulin with the CnA CaM-binding domain peptide and biophysical work on the regulatory domain show that this binding removes the autoinhibitory domain from the active site. Reason: Calmodulin binding is the activating input of calcineurin A and is directly shown with CnA peptides and the regulatory domain. Retained as a core MF that complements the catalytic activity. Supporting Evidence: PMID:27187005 this stabilization of the distal helix increases the activity of calcineurin PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. PMID:24191726 CaM binds CaN's regulatory domain (RD) and causes a conformational change that removes CaN's autoinhibitory domain (AID) from its catalytic site, activating CaN. |
| GO:0005515 protein binding | IPI PMID:34446558 SPATA33 localizes calcineurin to the mitochondria and regula... | REMOVE | Summary: SPATA33 binds calcineurin via a PQIIIT (PxIxIT-type) motif; the functional work concerns sperm calcineurin (PPP3CC/PPP3R2) in mouse. Reason: Docking-partner binding; uninformative for PPP3CA function. Supporting Evidence: PMID:34446558 we discovered that SPATA33 interacts with sperm calcineurin via a PQIIIT sequence |
| GO:0042104 positive regulation of activated T cell proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Ppp3ca: knockout T cells show defective antigen-specific proliferation. Reason: Knockout phenotype reflecting necessity of calcineurin-NFAT signaling for T cell activation; per project rule kept non-core. |
| GO:0023057 negative regulation of signaling | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS from mouse for negative regulation of signaling (UniProt: negatively regulates MAP3K14/NIK signaling, by similarity). Reason: Extremely broad term; PPP3CA both promotes and dampens different pathways depending on substrate. |
| GO:0050804 modulation of chemical synaptic transmission | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse; calcineurin is required for hippocampal homosynaptic depotentiation (UniProt, by similarity). Reason: Neuronal context; non-core. |
| GO:0008544 epidermis development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse knockout data: calcineurin A-alpha required for keratinocyte differentiation and epidermal superstructure. Reason: Knockout-phenotype developmental process; non-core. |
| GO:0030216 keratinocyte differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse knockout data on keratinocyte differentiation and survival. Reason: Knockout-phenotype developmental process; non-core. |
| GO:0005515 protein binding | IPI PMID:28881575 Overexpression of C16orf74 is involved in aggressive pancrea... | REMOVE | Summary: Thr44-phosphorylated C16orf74 binds PPP3CA via a PxIxIT-type PDIIIT motif in pancreatic cancer cells. Reason: Docking-motif partner binding; the PxIxIT-pocket interaction is generic to calcineurin substrates and regulators and is not captured informatively by protein binding. Supporting Evidence: PMID:28881575 the endogenous threonine 44 (T44)-phosphorylated form of C16orf74 interacted with the protein phosphatase 3 catalytic subunit alpha (PPP3CA) via the PDIIIT sequence |
| GO:0005886 plasma membrane | IDA PMID:28881575 Overexpression of C16orf74 is involved in aggressive pancrea... | KEEP AS NON CORE | Summary: PPP3CA is recruited to the plasma membrane by anchoring proteins, notably AKAP79/AKAP5 (FRET/colocalization at the plasma membrane), and by PMCA4b; this pool controls local Ca2+-calcineurin-NFAT signaling. Reason: Experimentally supported but scaffold-dependent; a minor, context-specific pool relative to cytosol. Supporting Evidence: PMID:28881575 the endogenous threonine 44 (T44)-phosphorylated form of C16orf74 interacted with the protein phosphatase 3 catalytic subunit alpha (PPP3CA) via the PDIIIT sequence PMID:22343722 with wildtype AKAP79-CFP resulted in colocalization of the YFP-labeled proteins with AKAP79 at the plasma membrane, and in FRET between CFP and YFP |
| GO:0097205 renal filtration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: knockout affects AQP2 processing/apical localization and kidney function. Reason: Tissue physiology inferred from knockout; non-core. |
| GO:0046878 positive regulation of saliva secretion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: knockout impairs secretion of salivary enzymes in submandibular gland. Reason: Tissue physiology inferred from knockout; non-core. |
| GO:0061006 regulation of cell proliferation involved in kidney morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: required for nephrogenic-zone cell-cycle homeostasis during postnatal kidney development. Reason: Knockout-phenotype developmental process; non-core. |
| GO:0090193 positive regulation of glomerulus development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: required for development of superficial glomeruli. Reason: Knockout-phenotype developmental process; non-core. |
| GO:0048741 skeletal muscle fiber development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: role in skeletal muscle fiber type specification via NFAT. Reason: Downstream developmental consequence of calcineurin-NFAT signaling; non-core. |
| GO:0045672 positive regulation of osteoclast differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: positively regulates osteoclast differentiation, probably via NFATC1. Reason: Downstream developmental consequence; non-core. |
| GO:0045669 positive regulation of osteoblast differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: positively regulates osteoblast differentiation and bone formation. Reason: Downstream developmental consequence; non-core. |
| GO:0033192 calmodulin-dependent protein phosphatase activity | IMP PMID:30254215 Novel calcineurin A (PPP3CA) variant associated with epileps... | ACCEPT | Summary: PPP3CA is the catalytic A-alpha subunit of calcineurin, a Ca2+/calmodulin-dependent protein serine/threonine phosphatase. Recombinant holoenzymes containing CnA-alpha dephosphorylate NFAT, Elk-1, DARPP-32 and RII peptide, and Ca2+/calmodulin binding to the CaM-binding domain displaces the autoinhibitory domain to activate the enzyme. Reason: Most specific and accurate MF for PPP3CA; consistent with direct kinetic assays on the alpha holoenzyme and with the structural activation mechanism. Core function. Supporting Evidence: PMID:30254215 c.1324C>T (p.(Gln442Ter)) results in constitutive activation of the enzyme PMID:19154138 all human CaN holoenzymes containing either the alpha, beta, or gamma isoform of the catalytic subunit (CaN alpha, beta, or gamma, respectively) were expressed for the first time PMID:19154138 CaN alpha dephosphorylates the transcription factor Elk-1 with 7- and 2-fold higher catalytic efficiencies than the beta and gamma isoforms, respectively PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. PMID:23468591 Calcineurin (CN) is a conserved Ca(2+)/calmodulin-dependent ser/thr phosphatase and the target of immunosuppressants, FK506 and cyclosporin A (CSA) |
| GO:0033173 calcineurin-NFAT signaling cascade | IMP PMID:26248042 Calcineurin Undergoes a Conformational Switch Evoked via Pep... | ACCEPT | Summary: PPP3CA dephosphorylates NFAT transcription factors (directly binding NFAT1 and NFATc1), enabling their nuclear translocation; this is the defining step of the calcineurin-NFAT signaling cascade. Reason: PPP3CA performs the enzymatic step that defines this pathway (GO:0033173 definition: NFAT activation as a consequence of dephosphorylation by Ca2+-activated calcineurin). Core process. Supporting Evidence: PMID:26248042 remodels the main regulatory site where NFATc transcription factors bind PMID:8631904 We also demonstrate a direct interaction between calcineurin and NFAT1 that is consistent with a direct enzyme-substrate relation between these two proteins PMID:23468591 One of the best-studied activities of CN is its dephosphorylation of the nuclear factor of activated T-cell family of transcription factors (NFATc1-c4), which allows NFAT to translocate to the nucleus where it induces the expression of genes required for T-cell activation PMID:27974827 Here we describe the crystal structure of CN in complex with its substrate NFATc1 |
| GO:0097720 calcineurin-mediated signaling | IMP PMID:11005320 Genetic conservation of the immunophilin-binding domains of ... | ACCEPT | Summary: Calcineurin-mediated signaling (parent of calcineurin-NFAT signaling cascade) is the Ca2+-triggered dephosphorylation of transcription factors by calcineurin, which PPP3CA catalyses. Note: the cited paper is a short SSCP polymorphism report (abstract-only here); the curator's experimental basis cannot be verified, but the function is well established for PPP3CA, so the annotation is accepted. Reason: PPP3CA performs the defining enzymatic step. Correct, slightly broader than GO:0033173, and also covers non-NFAT calcineurin targets. Supporting Evidence: PMID:11005320 Calcineurin is a dimeric protein consisting of distinct A (catalytic) and B (regulatory) subunits. PMID:23468591 One of the best-studied activities of CN is its dephosphorylation of the nuclear factor of activated T-cell family of transcription factors (NFATc1-c4), which allows NFAT to translocate to the nucleus where it induces the expression of genes required for T-cell activation |
| GO:0042060 wound healing | TAS PMID:18846255 Calsarcin-2 deficiency increases exercise capacity in mice t... | KEEP AS NON CORE | Summary: TAS from a calsarcin-2 knockout study of calcineurin/NFAT-driven fiber-type switching; the cached abstract does not discuss wound healing. Reason: Abstract-only; cannot verify the wound-healing statement in the full text, but the term is at most a downstream physiological context. Retained as non-core, deferring to the curator. Supporting Evidence: PMID:18846255 calsarcin-2 modulates exercise performance in vivo through regulation of calcineurin/NFAT activity |
| GO:0005737 cytoplasm | IDA PMID:15955804 The sarcolemmal calcium pump inhibits the calcineurin/nuclea... | ACCEPT | Summary: Calcineurin A-alpha is cytoplasmic; the alpha, beta and gamma holoenzymes show the same cytoplasmic distribution. Reason: Cytoplasm/cytosol is the principal compartment in which calcineurin encounters NFAT and other substrates. Supporting Evidence: PMID:15955804 The interaction domains were located to the catalytic domain of PMCA4b and the catalytic domain of the calcineurin A subunit. PMID:19154138 all CaN isoforms display the same cytoplasmic subcellular distribution |
| GO:0005886 plasma membrane | IDA PMID:15955804 The sarcolemmal calcium pump inhibits the calcineurin/nuclea... | KEEP AS NON CORE | Summary: PPP3CA is recruited to the plasma membrane by anchoring proteins, notably AKAP79/AKAP5 (FRET/colocalization at the plasma membrane), and by PMCA4b; this pool controls local Ca2+-calcineurin-NFAT signaling. Reason: Experimentally supported but scaffold-dependent; a minor, context-specific pool relative to cytosol. Supporting Evidence: PMID:15955804 The interaction domains were located to the catalytic domain of PMCA4b and the catalytic domain of the calcineurin A subunit. PMID:22343722 with wildtype AKAP79-CFP resulted in colocalization of the YFP-labeled proteins with AKAP79 at the plasma membrane, and in FRET between CFP and YFP |
| GO:0019897 extrinsic component of plasma membrane | IC PMID:15955804 The sarcolemmal calcium pump inhibits the calcineurin/nuclea... | KEEP AS NON CORE | Summary: PMCA4b binds the catalytic domain of calcineurin A, recruiting a pool of calcineurin to the inner face of the plasma membrane. Reason: Peripheral membrane association via partners; non-core. Supporting Evidence: PMID:15955804 The interaction domains were located to the catalytic domain of PMCA4b and the catalytic domain of the calcineurin A subunit. |
| GO:0033173 calcineurin-NFAT signaling cascade | IMP PMID:15955804 The sarcolemmal calcium pump inhibits the calcineurin/nuclea... | ACCEPT | Summary: PPP3CA dephosphorylates NFAT transcription factors (directly binding NFAT1 and NFATc1), enabling their nuclear translocation; this is the defining step of the calcineurin-NFAT signaling cascade. Reason: PPP3CA performs the enzymatic step that defines this pathway (GO:0033173 definition: NFAT activation as a consequence of dephosphorylation by Ca2+-activated calcineurin). Core process. Supporting Evidence: PMID:15955804 The interaction domains were located to the catalytic domain of PMCA4b and the catalytic domain of the calcineurin A subunit. PMID:8631904 We also demonstrate a direct interaction between calcineurin and NFAT1 that is consistent with a direct enzyme-substrate relation between these two proteins PMID:23468591 One of the best-studied activities of CN is its dephosphorylation of the nuclear factor of activated T-cell family of transcription factors (NFATc1-c4), which allows NFAT to translocate to the nucleus where it induces the expression of genes required for T-cell activation PMID:27974827 Here we describe the crystal structure of CN in complex with its substrate NFATc1 |
| GO:0051117 ATPase binding | IPI PMID:15955804 The sarcolemmal calcium pump inhibits the calcineurin/nuclea... | KEEP AS NON CORE | Summary: The catalytic domain of calcineurin A binds the catalytic domain of the plasma membrane Ca2+-ATPase PMCA4b, which inhibits calcineurin/NFAT signaling. Reason: Specific, experimentally supported partner interaction (more informative than protein binding) but a regulatory input rather than a core activity. Supporting Evidence: PMID:15955804 The interaction domains were located to the catalytic domain of PMCA4b and the catalytic domain of the calcineurin A subunit. PMID:15955804 Endogenous calcineurin activity, assessed by measuring the transcriptional activity of its best characterized substrate, NFAT, was significantly inhibited by 60% in the presence of ectopic PMCA4b. |
| GO:0005515 protein binding | IPI PMID:30611118 Mitogenic Signals Stimulate the CREB Coactivator CRTC3 throu... | REMOVE | Summary: Mouse CRTC2 associates with calcineurin; CRTCs are calcineurin substrates (dephosphorylation of 14-3-3 sites). Reason: Enzyme-substrate binding; captured by the phosphatase activity, not by protein binding. Supporting Evidence: PMID:30611118 CRTC1 and CRTC2 associate selectively with the calcium-dependent phosphatase calcineurin |
| GO:0043403 skeletal muscle tissue regeneration | TAS PMID:18846255 Calsarcin-2 deficiency increases exercise capacity in mice t... | KEEP AS NON CORE | Summary: TAS from a calsarcin-2 knockout study showing calcineurin/NFAT control of skeletal muscle fiber composition. Reason: Muscle physiology context; non-core. Supporting Evidence: PMID:18846255 calsarcin-2 modulates exercise performance in vivo through regulation of calcineurin/NFAT activity |
| GO:0045785 positive regulation of cell adhesion | IMP PMID:21785830 The effect of down regulation of calcineurin AΞ± by lentivira... | MARK AS OVER ANNOTATED | Summary: RNAi knockdown of CnA-alpha in a small-cell lung cancer line reduced adhesion to bone matrix. Reason: Single cancer cell-line phenotype; not a general function of PPP3CA. Supporting Evidence: PMID:21785830 reduce the cell migration and invasion, and inhibit cells adhering to bone matrix |
| GO:0030335 positive regulation of cell migration | IMP PMID:21785830 The effect of down regulation of calcineurin AΞ± by lentivira... | MARK AS OVER ANNOTATED | Summary: RNAi knockdown of CnA-alpha in SCLC cells reduced migration and invasion. Reason: Cancer cell-line phenotype; pleiotropic downstream effect. Supporting Evidence: PMID:21785830 reduce the cell migration and invasion, and inhibit cells adhering to bone matrix |
| GO:0030335 positive regulation of cell migration | IMP PMID:20422345 Calcineurin promotes proliferation, migration, and invasion ... | MARK AS OVER ANNOTATED | Summary: Overexpression of CnA-alpha in SBC-3 SCLC cells promoted migration and invasion. Reason: Cancer cell-line overexpression phenotype; pleiotropic downstream effect. Supporting Evidence: PMID:20422345 Transfection with the CnAalpha gene promoted cell migration and invasion. |
| GO:0005515 protein binding | IPI PMID:18218901 NFAT binding and regulation of T cell activation by the cyto... | REMOVE | Summary: NFATC2 (NFAT1) binds calcineurin; Homer proteins compete with calcineurin for NFAT binding in T cells. Reason: Enzyme-substrate binding; the informative statement is the NFAT phosphatase activity and calcineurin-NFAT signaling, which are annotated. Supporting Evidence: PMID:18218901 This is achieved through binding of nuclear factor of activated T cells (NFAT) and by competing with calcineurin. |
| GO:0005515 protein binding | IPI PMID:12809556 Phosphorylation of calcipressin 1 increases its ability to i... | REMOVE | Summary: RCAN1 (calcipressin 1) binds calcineurin A and inhibits NFAT-mediated transcription. Reason: Inhibitor binding; informative term belongs on RCAN1 (calcineurin inhibitor activity). Supporting Evidence: PMID:12809556 This polypeptide is able to interact with calcineurin A and to inhibit NF-AT-mediated transcriptional activation. |
| GO:0005515 protein binding | IPI PMID:12218175 Crystal structure of calcineurin-cyclophilin-cyclosporin sho... | REMOVE | Summary: Crystal structure of calcineurin (CnA/CnB) with cyclophilin A-cyclosporin A; CypA contacts CnA only in the drug-bound complex. Reason: Drug-dependent immunophilin binding and CnA-CnB binding are not informative MFs; CnB binding is captured by calcineurin complex. Supporting Evidence: PMID:12218175 The CyPA-CsA complex binds to a composite surface formed by the catalytic and regulatory subunits of CN |
| GO:0005515 protein binding | IPI PMID:26248042 Calcineurin Undergoes a Conformational Switch Evoked via Pep... | REMOVE | Summary: NFATC2 binding to calcineurin in a structural/conformational study. Reason: Enzyme-substrate binding; uninformative as protein binding. Supporting Evidence: PMID:26248042 remodels the main regulatory site where NFATc transcription factors bind |
| GO:0005515 protein binding | IPI PMID:27974827 Investigating the human Calcineurin Interaction Network usin... | REMOVE | Summary: Crystal structure of the CnA/CnB heterodimer bound to an NFATc1 LxVP peptide. Reason: PPP3R1 binding is the calcineurin A/B heterodimer interaction already captured by part_of calcineurin complex (GO:0005955); generic protein binding adds no information. Supporting Evidence: PMID:27974827 Here we describe the crystal structure of CN in complex with its substrate NFATc1 |
| GO:0005516 calmodulin binding | IDA PMID:19404396 Domain swapping and different oligomeric States for the comp... | ACCEPT | Summary: PPP3CA binds Ca2+/calmodulin through the calmodulin-binding domain in its regulatory region; crystal structures of calmodulin with the CnA CaM-binding domain peptide and biophysical work on the regulatory domain show that this binding removes the autoinhibitory domain from the active site. Reason: Calmodulin binding is the activating input of calcineurin A and is directly shown with CnA peptides and the regulatory domain. Retained as a core MF that complements the catalytic activity. Supporting Evidence: PMID:19404396 a high-resolution crystal structure of a complex between CaM and the CaM-binding domain of calcineurin A PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. PMID:24191726 CaM binds CaN's regulatory domain (RD) and causes a conformational change that removes CaN's autoinhibitory domain (AID) from its catalytic site, activating CaN. |
| GO:0005737 cytoplasm | IDA PMID:19154138 The proline-rich N-terminal sequence of calcineurin Abeta de... | ACCEPT | Summary: Calcineurin A-alpha is cytoplasmic; the alpha, beta and gamma holoenzymes show the same cytoplasmic distribution. Reason: Cytoplasm/cytosol is the principal compartment in which calcineurin encounters NFAT and other substrates. Supporting Evidence: PMID:19154138 all human CaN holoenzymes containing either the alpha, beta, or gamma isoform of the catalytic subunit (CaN alpha, beta, or gamma, respectively) were expressed for the first time |
| GO:0005737 cytoplasm | IDA PMID:22343722 Balanced interactions of calcineurin with AKAP79 regulate Ca... | ACCEPT | Summary: Calcineurin A-alpha is cytoplasmic; the alpha, beta and gamma holoenzymes show the same cytoplasmic distribution. Reason: Cytoplasm/cytosol is the principal compartment in which calcineurin encounters NFAT and other substrates. Supporting Evidence: PMID:22343722 only a rather narrow window of CN-AKAP79 affinities is compatible with normal NFAT signaling PMID:19154138 all CaN isoforms display the same cytoplasmic subcellular distribution |
| GO:0005955 calcineurin complex | IDA PMID:12218175 Crystal structure of calcineurin-cyclophilin-cyclosporin sho... | ACCEPT | Summary: PPP3CA is the catalytic A subunit of the calcineurin heterodimer (CnA/CnB, with PPP3R1); crystal structures of human calcineurin show the catalytic and regulatory subunits forming the composite surface recognized by immunophilin-drug complexes. Reason: Complex membership is structurally established and defines PPP3CA activity. Core cellular component, consistent with the PPP3CB and PPP3R1 reviews (GO:0005955). Supporting Evidence: PMID:12218175 The CyPA-CsA complex binds to a composite surface formed by the catalytic and regulatory subunits of CN PMID:8524402 In the native CaN structure, an auto-inhibitory element binds at the Zn/Fe-containing active site. PMID:12357034 We report the crystal structure of a Cyp/CsA/Cn ternary complex |
| GO:0005955 calcineurin complex | IDA PMID:22343722 Balanced interactions of calcineurin with AKAP79 regulate Ca... | ACCEPT | Summary: PPP3CA is the catalytic A subunit of the calcineurin heterodimer (CnA/CnB, with PPP3R1); crystal structures of human calcineurin show the catalytic and regulatory subunits forming the composite surface recognized by immunophilin-drug complexes. Reason: Complex membership is structurally established and defines PPP3CA activity. Core cellular component, consistent with the PPP3CB and PPP3R1 reviews (GO:0005955). Supporting Evidence: PMID:22343722 only a rather narrow window of CN-AKAP79 affinities is compatible with normal NFAT signaling PMID:8524402 In the native CaN structure, an auto-inhibitory element binds at the Zn/Fe-containing active site. PMID:12218175 The CyPA-CsA complex binds to a composite surface formed by the catalytic and regulatory subunits of CN PMID:12357034 We report the crystal structure of a Cyp/CsA/Cn ternary complex |
| GO:0005955 calcineurin complex | IDA PMID:23468591 The molecular mechanism of substrate engagement and immunosu... | ACCEPT | Summary: PPP3CA is the catalytic A subunit of the calcineurin heterodimer (CnA/CnB, with PPP3R1); crystal structures of human calcineurin show the catalytic and regulatory subunits forming the composite surface recognized by immunophilin-drug complexes. Reason: Complex membership is structurally established and defines PPP3CA activity. Core cellular component, consistent with the PPP3CB and PPP3R1 reviews (GO:0005955). Supporting Evidence: PMID:23468591 Calcineurin (CN) is a conserved Ca(2+)/calmodulin-dependent ser/thr phosphatase and the target of immunosuppressants, FK506 and cyclosporin A (CSA) PMID:8524402 In the native CaN structure, an auto-inhibitory element binds at the Zn/Fe-containing active site. PMID:12218175 The CyPA-CsA complex binds to a composite surface formed by the catalytic and regulatory subunits of CN PMID:12357034 We report the crystal structure of a Cyp/CsA/Cn ternary complex |
| GO:0005955 calcineurin complex | IDA PMID:27974827 Investigating the human Calcineurin Interaction Network usin... | ACCEPT | Summary: PPP3CA is the catalytic A subunit of the calcineurin heterodimer (CnA/CnB, with PPP3R1); crystal structures of human calcineurin show the catalytic and regulatory subunits forming the composite surface recognized by immunophilin-drug complexes. Reason: Complex membership is structurally established and defines PPP3CA activity. Core cellular component, consistent with the PPP3CB and PPP3R1 reviews (GO:0005955). Supporting Evidence: PMID:27974827 Here we describe the crystal structure of CN in complex with its substrate NFATc1 PMID:8524402 In the native CaN structure, an auto-inhibitory element binds at the Zn/Fe-containing active site. PMID:12218175 The CyPA-CsA complex binds to a composite surface formed by the catalytic and regulatory subunits of CN PMID:12357034 We report the crystal structure of a Cyp/CsA/Cn ternary complex |
| GO:0006470 protein dephosphorylation | IDA PMID:19154138 The proline-rich N-terminal sequence of calcineurin Abeta de... | ACCEPT | Summary: PPP3CA dephosphorylates protein substrates including NFAT, Elk-1, DNM1L Ser637, SSH1L and KLHL3 Ser433. Reason: Direct biochemical output of the catalytic activity; acceptable process term. Supporting Evidence: PMID:19154138 all human CaN holoenzymes containing either the alpha, beta, or gamma isoform of the catalytic subunit (CaN alpha, beta, or gamma, respectively) were expressed for the first time PMID:18838687 Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria PMID:15671020 calcineurin dephosphorylated SSH1L and increased the cofilin-phosphatase activity of SSH1L in cell-free assays PMID:30718414 We report herein that calcineurin normally dephosphorylates KLHL3S433-P and that this action is inhibited by CNIs |
| GO:0009898 cytoplasmic side of plasma membrane | IDA PMID:22343722 Balanced interactions of calcineurin with AKAP79 regulate Ca... | KEEP AS NON CORE | Summary: AKAP79 anchors calcineurin at the plasma membrane (colocalization and FRET); colocalizes_with cytoplasmic side of plasma membrane. Reason: Scaffold-dependent pool; non-core. Supporting Evidence: PMID:22343722 with wildtype AKAP79-CFP resulted in colocalization of the YFP-labeled proteins with AKAP79 at the plasma membrane, and in FRET between CFP and YFP |
| GO:0033173 calcineurin-NFAT signaling cascade | IDA PMID:19154138 The proline-rich N-terminal sequence of calcineurin Abeta de... | ACCEPT | Summary: PPP3CA dephosphorylates NFAT transcription factors (directly binding NFAT1 and NFATc1), enabling their nuclear translocation; this is the defining step of the calcineurin-NFAT signaling cascade. Reason: PPP3CA performs the enzymatic step that defines this pathway (GO:0033173 definition: NFAT activation as a consequence of dephosphorylation by Ca2+-activated calcineurin). Core process. Supporting Evidence: PMID:19154138 all human CaN holoenzymes containing either the alpha, beta, or gamma isoform of the catalytic subunit (CaN alpha, beta, or gamma, respectively) were expressed for the first time PMID:8631904 We also demonstrate a direct interaction between calcineurin and NFAT1 that is consistent with a direct enzyme-substrate relation between these two proteins PMID:23468591 One of the best-studied activities of CN is its dephosphorylation of the nuclear factor of activated T-cell family of transcription factors (NFATc1-c4), which allows NFAT to translocate to the nucleus where it induces the expression of genes required for T-cell activation PMID:27974827 Here we describe the crystal structure of CN in complex with its substrate NFATc1 |
| GO:0033173 calcineurin-NFAT signaling cascade | IMP PMID:22343722 Balanced interactions of calcineurin with AKAP79 regulate Ca... | ACCEPT | Summary: PPP3CA dephosphorylates NFAT transcription factors (directly binding NFAT1 and NFATc1), enabling their nuclear translocation; this is the defining step of the calcineurin-NFAT signaling cascade. Reason: PPP3CA performs the enzymatic step that defines this pathway (GO:0033173 definition: NFAT activation as a consequence of dephosphorylation by Ca2+-activated calcineurin). Core process. Supporting Evidence: PMID:22343722 only a rather narrow window of CN-AKAP79 affinities is compatible with normal NFAT signaling PMID:8631904 We also demonstrate a direct interaction between calcineurin and NFAT1 that is consistent with a direct enzyme-substrate relation between these two proteins PMID:23468591 One of the best-studied activities of CN is its dephosphorylation of the nuclear factor of activated T-cell family of transcription factors (NFATc1-c4), which allows NFAT to translocate to the nucleus where it induces the expression of genes required for T-cell activation PMID:27974827 Here we describe the crystal structure of CN in complex with its substrate NFATc1 |
| GO:0033173 calcineurin-NFAT signaling cascade | IMP PMID:23468591 The molecular mechanism of substrate engagement and immunosu... | ACCEPT | Summary: PPP3CA dephosphorylates NFAT transcription factors (directly binding NFAT1 and NFATc1), enabling their nuclear translocation; this is the defining step of the calcineurin-NFAT signaling cascade. Reason: PPP3CA performs the enzymatic step that defines this pathway (GO:0033173 definition: NFAT activation as a consequence of dephosphorylation by Ca2+-activated calcineurin). Core process. Supporting Evidence: PMID:23468591 Calcineurin (CN) is a conserved Ca(2+)/calmodulin-dependent ser/thr phosphatase and the target of immunosuppressants, FK506 and cyclosporin A (CSA) PMID:8631904 We also demonstrate a direct interaction between calcineurin and NFAT1 that is consistent with a direct enzyme-substrate relation between these two proteins PMID:27974827 Here we describe the crystal structure of CN in complex with its substrate NFATc1 |
| GO:0033192 calmodulin-dependent protein phosphatase activity | IDA PMID:19154138 The proline-rich N-terminal sequence of calcineurin Abeta de... | ACCEPT | Summary: PPP3CA is the catalytic A-alpha subunit of calcineurin, a Ca2+/calmodulin-dependent protein serine/threonine phosphatase. Recombinant holoenzymes containing CnA-alpha dephosphorylate NFAT, Elk-1, DARPP-32 and RII peptide, and Ca2+/calmodulin binding to the CaM-binding domain displaces the autoinhibitory domain to activate the enzyme. Reason: Most specific and accurate MF for PPP3CA; consistent with direct kinetic assays on the alpha holoenzyme and with the structural activation mechanism. Core function. Supporting Evidence: PMID:19154138 all human CaN holoenzymes containing either the alpha, beta, or gamma isoform of the catalytic subunit (CaN alpha, beta, or gamma, respectively) were expressed for the first time PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. PMID:23468591 Calcineurin (CN) is a conserved Ca(2+)/calmodulin-dependent ser/thr phosphatase and the target of immunosuppressants, FK506 and cyclosporin A (CSA) |
| GO:0033192 calmodulin-dependent protein phosphatase activity | IDA PMID:23468591 The molecular mechanism of substrate engagement and immunosu... | ACCEPT | Summary: PPP3CA is the catalytic A-alpha subunit of calcineurin, a Ca2+/calmodulin-dependent protein serine/threonine phosphatase. Recombinant holoenzymes containing CnA-alpha dephosphorylate NFAT, Elk-1, DARPP-32 and RII peptide, and Ca2+/calmodulin binding to the CaM-binding domain displaces the autoinhibitory domain to activate the enzyme. Reason: Most specific and accurate MF for PPP3CA; consistent with direct kinetic assays on the alpha holoenzyme and with the structural activation mechanism. Core function. Supporting Evidence: PMID:23468591 Calcineurin (CN) is a conserved Ca(2+)/calmodulin-dependent ser/thr phosphatase and the target of immunosuppressants, FK506 and cyclosporin A (CSA) PMID:19154138 all human CaN holoenzymes containing either the alpha, beta, or gamma isoform of the catalytic subunit (CaN alpha, beta, or gamma, respectively) were expressed for the first time PMID:19154138 CaN alpha dephosphorylates the transcription factor Elk-1 with 7- and 2-fold higher catalytic efficiencies than the beta and gamma isoforms, respectively PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. |
| GO:0043197 dendritic spine | IDA PMID:22343722 Balanced interactions of calcineurin with AKAP79 regulate Ca... | KEEP AS NON CORE | Summary: AKAP79/150 anchors calcineurin in dendritic spines of hippocampal neurons (FRAP shows AKAP-dependent immobilization of CN in spines). Reason: Neuron-specific localization; correct but not universal. Supporting Evidence: PMID:22343722 only a rather narrow window of CN-AKAP79 affinities is compatible with normal NFAT signaling |
| GO:0005515 protein binding | IPI PMID:12357034 Crystal structure of human calcineurin complexed with cyclos... | REMOVE | Summary: Crystal structure of Cyp/CsA/Cn ternary complex. Reason: Drug-dependent immunophilin binding and CnA-CnB binding are not informative MFs; CnB binding is captured by calcineurin complex. Supporting Evidence: PMID:12357034 We report the crystal structure of a Cyp/CsA/Cn ternary complex |
| GO:0005955 calcineurin complex | IDA PMID:12357034 Crystal structure of human calcineurin complexed with cyclos... | ACCEPT | Summary: PPP3CA is the catalytic A subunit of the calcineurin heterodimer (CnA/CnB, with PPP3R1); crystal structures of human calcineurin show the catalytic and regulatory subunits forming the composite surface recognized by immunophilin-drug complexes. Reason: Complex membership is structurally established and defines PPP3CA activity. Core cellular component, consistent with the PPP3CB and PPP3R1 reviews (GO:0005955). Supporting Evidence: PMID:12357034 We report the crystal structure of a Cyp/CsA/Cn ternary complex PMID:8524402 In the native CaN structure, an auto-inhibitory element binds at the Zn/Fe-containing active site. PMID:12218175 The CyPA-CsA complex binds to a composite surface formed by the catalytic and regulatory subunits of CN |
| GO:0005515 protein binding | IPI PMID:22688515 Na(+)/H(+) exchanger 1 directly binds to calcineurin A and a... | REMOVE | Summary: NHE1 (SLC9A1) binds CnA directly through a PxIxIT-like PVITID motif and promotes CaN/NFAT signaling in cardiomyocytes. Reason: Docking-partner binding; uninformative as protein binding (NHE1 is also a downstream target, PMID:31375679). Supporting Evidence: PMID:22688515 Direct binding of CaN to the (715)PVITID(720) sequence of NHE1, which resembles the consensus CaN-binding motif (PXIXIT), was observed. |
| GO:0005955 calcineurin complex | IDA PMID:22688515 Na(+)/H(+) exchanger 1 directly binds to calcineurin A and a... | ACCEPT | Summary: PPP3CA is the catalytic A subunit of the calcineurin heterodimer (CnA/CnB, with PPP3R1); crystal structures of human calcineurin show the catalytic and regulatory subunits forming the composite surface recognized by immunophilin-drug complexes. Reason: Complex membership is structurally established and defines PPP3CA activity. Core cellular component, consistent with the PPP3CB and PPP3R1 reviews (GO:0005955). Supporting Evidence: PMID:22688515 Direct binding of CaN to the (715)PVITID(720) sequence of NHE1, which resembles the consensus CaN-binding motif (PXIXIT), was observed. PMID:8524402 In the native CaN structure, an auto-inhibitory element binds at the Zn/Fe-containing active site. PMID:12218175 The CyPA-CsA complex binds to a composite surface formed by the catalytic and regulatory subunits of CN PMID:12357034 We report the crystal structure of a Cyp/CsA/Cn ternary complex |
| GO:0033173 calcineurin-NFAT signaling cascade | IDA PMID:22688515 Na(+)/H(+) exchanger 1 directly binds to calcineurin A and a... | ACCEPT | Summary: PPP3CA dephosphorylates NFAT transcription factors (directly binding NFAT1 and NFATc1), enabling their nuclear translocation; this is the defining step of the calcineurin-NFAT signaling cascade. Reason: PPP3CA performs the enzymatic step that defines this pathway (GO:0033173 definition: NFAT activation as a consequence of dephosphorylation by Ca2+-activated calcineurin). Core process. Supporting Evidence: PMID:22688515 Direct binding of CaN to the (715)PVITID(720) sequence of NHE1, which resembles the consensus CaN-binding motif (PXIXIT), was observed. PMID:8631904 We also demonstrate a direct interaction between calcineurin and NFAT1 that is consistent with a direct enzyme-substrate relation between these two proteins PMID:23468591 One of the best-studied activities of CN is its dephosphorylation of the nuclear factor of activated T-cell family of transcription factors (NFATc1-c4), which allows NFAT to translocate to the nucleus where it induces the expression of genes required for T-cell activation PMID:27974827 Here we describe the crystal structure of CN in complex with its substrate NFATc1 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:22688515 Na(+)/H(+) exchanger 1 directly binds to calcineurin A and a... | KEEP AS NON CORE | Summary: NHE1 binding stimulated CaN/NFAT-dependent transcription (NFAT reporter, hypertrophic genes); PPP3CA acts indirectly via NFAT dephosphorylation. Reason: Indirect consequence of NFAT activation; PPP3CA is not a transcription regulator itself. Supporting Evidence: PMID:22688515 Direct binding of CaN to the (715)PVITID(720) sequence of NHE1, which resembles the consensus CaN-binding motif (PXIXIT), was observed. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2025890 | ACCEPT | Summary: Calcineurin is a soluble cytoplasmic phosphatase that dephosphorylates cytosolic NFAT and other substrates (e.g. DNM1L) in response to Ca2+ rises. Reason: Cytosol is the principal site of PPP3CA activity. Supporting Evidence: PMID:19154138 all CaN isoforms display the same cytoplasmic subcellular distribution PMID:18838687 Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730849 | ACCEPT | Summary: Calcineurin is a soluble cytoplasmic phosphatase that dephosphorylates cytosolic NFAT and other substrates (e.g. DNM1L) in response to Ca2+ rises. Reason: Cytosol is the principal site of PPP3CA activity. Supporting Evidence: PMID:19154138 all CaN isoforms display the same cytoplasmic subcellular distribution PMID:18838687 Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730867 | ACCEPT | Summary: Calcineurin is a soluble cytoplasmic phosphatase that dephosphorylates cytosolic NFAT and other substrates (e.g. DNM1L) in response to Ca2+ rises. Reason: Cytosol is the principal site of PPP3CA activity. Supporting Evidence: PMID:19154138 all CaN isoforms display the same cytoplasmic subcellular distribution PMID:18838687 Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730872 | ACCEPT | Summary: Calcineurin is a soluble cytoplasmic phosphatase that dephosphorylates cytosolic NFAT and other substrates (e.g. DNM1L) in response to Ca2+ rises. Reason: Cytosol is the principal site of PPP3CA activity. Supporting Evidence: PMID:19154138 all CaN isoforms display the same cytoplasmic subcellular distribution PMID:18838687 Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria |
| GO:0005829 cytosol | TAS Reactome:R-HSA-4551451 | ACCEPT | Summary: Calcineurin is a soluble cytoplasmic phosphatase that dephosphorylates cytosolic NFAT and other substrates (e.g. DNM1L) in response to Ca2+ rises. Reason: Cytosol is the principal site of PPP3CA activity. Supporting Evidence: PMID:19154138 all CaN isoforms display the same cytoplasmic subcellular distribution PMID:18838687 Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria |
| GO:0005829 cytosol | TAS Reactome:R-HSA-4551465 | ACCEPT | Summary: Calcineurin is a soluble cytoplasmic phosphatase that dephosphorylates cytosolic NFAT and other substrates (e.g. DNM1L) in response to Ca2+ rises. Reason: Cytosol is the principal site of PPP3CA activity. Supporting Evidence: PMID:19154138 all CaN isoforms display the same cytoplasmic subcellular distribution PMID:18838687 Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2730867 | KEEP AS NON CORE | Summary: Reactome models translocation of the CaN:CaM:NFAT complex to the nucleus. Reason: Pathway-model localization; calcineurin acts mainly in the cytoplasm and a nuclear pool is not well established experimentally. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-4551465 | KEEP AS NON CORE | Summary: Reactome models translocation of the NFATC1:CaN:CaM complex to the nucleus. Reason: Pathway-model localization; non-core. |
| GO:0006470 protein dephosphorylation | IDA PMID:18815128 CHP2 activates the calcineurin/nuclear factor of activated T... | ACCEPT | Summary: PPP3CA dephosphorylates protein substrates including NFAT, Elk-1, DNM1L Ser637, SSH1L and KLHL3 Ser433. Reason: Direct biochemical output of the catalytic activity; acceptable process term. Supporting Evidence: PMID:18815128 CHP2 was able to bind to and stimulate the phosphatase activity of calcineurin A PMID:18838687 Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria PMID:15671020 calcineurin dephosphorylated SSH1L and increased the cofilin-phosphatase activity of SSH1L in cell-free assays PMID:30718414 We report herein that calcineurin normally dephosphorylates KLHL3S433-P and that this action is inhibited by CNIs |
| GO:0033192 calmodulin-dependent protein phosphatase activity | IDA PMID:18815128 CHP2 activates the calcineurin/nuclear factor of activated T... | ACCEPT | Summary: PPP3CA is the catalytic A-alpha subunit of calcineurin, a Ca2+/calmodulin-dependent protein serine/threonine phosphatase. Recombinant holoenzymes containing CnA-alpha dephosphorylate NFAT, Elk-1, DARPP-32 and RII peptide, and Ca2+/calmodulin binding to the CaM-binding domain displaces the autoinhibitory domain to activate the enzyme. Reason: Most specific and accurate MF for PPP3CA; consistent with direct kinetic assays on the alpha holoenzyme and with the structural activation mechanism. Core function. Supporting Evidence: PMID:18815128 CHP2 was able to bind to and stimulate the phosphatase activity of calcineurin A PMID:19154138 all human CaN holoenzymes containing either the alpha, beta, or gamma isoform of the catalytic subunit (CaN alpha, beta, or gamma, respectively) were expressed for the first time PMID:19154138 CaN alpha dephosphorylates the transcription factor Elk-1 with 7- and 2-fold higher catalytic efficiencies than the beta and gamma isoforms, respectively PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. PMID:23468591 Calcineurin (CN) is a conserved Ca(2+)/calmodulin-dependent ser/thr phosphatase and the target of immunosuppressants, FK506 and cyclosporin A (CSA) |
| GO:0051592 response to calcium ion | IDA PMID:18815128 CHP2 activates the calcineurin/nuclear factor of activated T... | KEEP AS NON CORE | Summary: Calcineurin A activity responds to Ca2+ through CnB, CHP2 and calmodulin; the cited study shows CHP2 binding stimulates CnA phosphatase activity and NFAT signaling. Reason: Response to calcium ion is a broad stimulus-response term; the Ca2+-dependence of PPP3CA is better captured by calmodulin-dependent protein phosphatase activity and calcineurin-mediated signaling. Changed from ACCEPT. Supporting Evidence: PMID:18815128 CHP2 was able to bind to and stimulate the phosphatase activity of calcineurin A |
| GO:0005516 calmodulin binding | IDA PMID:11005320 Genetic conservation of the immunophilin-binding domains of ... | ACCEPT | Summary: PPP3CA binds Ca2+/calmodulin through the calmodulin-binding domain in its regulatory region; crystal structures of calmodulin with the CnA CaM-binding domain peptide and biophysical work on the regulatory domain show that this binding removes the autoinhibitory domain from the active site. Note: the cited paper is a short SSCP polymorphism report (abstract-only here); the curator's experimental basis cannot be verified, but the function is well established for PPP3CA, so the annotation is accepted. Reason: Calmodulin binding is the activating input of calcineurin A and is directly shown with CnA peptides and the regulatory domain. Retained as a core MF that complements the catalytic activity. Supporting Evidence: PMID:11005320 Calcineurin is a dimeric protein consisting of distinct A (catalytic) and B (regulatory) subunits. PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. PMID:24191726 CaM binds CaN's regulatory domain (RD) and causes a conformational change that removes CaN's autoinhibitory domain (AID) from its catalytic site, activating CaN. |
| GO:0019899 enzyme binding | IDA PMID:11005320 Genetic conservation of the immunophilin-binding domains of ... | UNDECIDED | Summary: Enzyme binding (IDA) attributed to a short report on SSCP polymorphism screening of the immunophilin/CnB/CaM-binding region of CNA1 and CNA2. The abstract describes no binding experiment. Reason: Abstract-only; cannot verify the experimental basis. Partner not specified. Not removed because the full text has not been read. Supporting Evidence: PMID:11005320 Calcineurin is a dimeric protein consisting of distinct A (catalytic) and B (regulatory) subunits. |
| GO:0042110 T cell activation | TAS PMID:11005320 Genetic conservation of the immunophilin-binding domains of ... | KEEP AS NON CORE | Summary: TAS: calcineurin plays a critical role in Ca2+-dependent T lymphocyte activation, through NFAT dephosphorylation. Reason: Correct physiological context; the specific calcineurin-NFAT signaling cascade is the core term. T cell activation is one of several contexts (immune, cardiac, neuronal, renal). Supporting Evidence: PMID:11005320 Calcineurin a calmodulin-dependent phosphatase plays a critical role in calcium-dependent activation of T-lymphocytes |
| GO:0046983 protein dimerization activity | IPI PMID:11005320 Genetic conservation of the immunophilin-binding domains of ... | UNDECIDED | Summary: Protein dimerization activity (IPI, with PPP3CB and with PPP3CA itself) attributed to an SSCP polymorphism study; the abstract only states as background that calcineurin is an A/B heterodimer and reports no binding assay. Reason: Abstract-only, cannot verify. CnA-CnA or CnA-alpha/CnA-beta dimerization is not an established property of calcineurin; the A/B heterodimer is captured by calcineurin complex. Changed from REMOVE because the full text was not read. Supporting Evidence: PMID:11005320 Calcineurin is a dimeric protein consisting of distinct A (catalytic) and B (regulatory) subunits. |
| GO:0016311 dephosphorylation | TAS PMID:2556704 Cloning of human calcineurin A: evidence for two isozymes an... | MODIFY | Summary: Dephosphorylation (TAS) citing the 1989 cloning paper on human calcineurin A, whose clones are the two PPP3CB (calcineurin A-beta) splice isoforms, not PPP3CA. Reason: Correct but general; protein dephosphorylation (GO:0006470) is the accurate process for a protein phosphatase. The cited paper describes PPP3CB, so the support here is PPP3CA-specific enzymology from another paper; the reference is flagged upstream. Proposed replacements: protein dephosphorylation Supporting Evidence: PMID:19154138 CaN alpha dephosphorylates the transcription factor Elk-1 with 7- and 2-fold higher catalytic efficiencies than the beta and gamma isoforms, respectively |
| GO:0033192 calmodulin-dependent protein phosphatase activity | TAS PMID:2556704 Cloning of human calcineurin A: evidence for two isozymes an... | ACCEPT | Summary: PPP3CA is the catalytic A-alpha subunit of calcineurin, a Ca2+/calmodulin-dependent protein serine/threonine phosphatase. Recombinant holoenzymes containing CnA-alpha dephosphorylate NFAT, Elk-1, DARPP-32 and RII peptide, and Ca2+/calmodulin binding to the CaM-binding domain displaces the autoinhibitory domain to activate the enzyme. Reason: Most specific and accurate MF for PPP3CA; consistent with direct kinetic assays on the alpha holoenzyme and with the structural activation mechanism. Core function. The cited cloning paper (PMID:2556704) describes PPP3CB isoforms, not PPP3CA, so it is not used as support and the reference is flagged upstream. Supporting Evidence: PMID:19154138 all human CaN holoenzymes containing either the alpha, beta, or gamma isoform of the catalytic subunit (CaN alpha, beta, or gamma, respectively) were expressed for the first time PMID:19154138 CaN alpha dephosphorylates the transcription factor Elk-1 with 7- and 2-fold higher catalytic efficiencies than the beta and gamma isoforms, respectively PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. PMID:23468591 Calcineurin (CN) is a conserved Ca(2+)/calmodulin-dependent ser/thr phosphatase and the target of immunosuppressants, FK506 and cyclosporin A (CSA) |
| GO:0005515 protein binding | IPI PMID:18838687 Dephosphorylation by calcineurin regulates translocation of ... | REMOVE | Summary: DNM1L/Drp1 interacts with calcineurin and is dephosphorylated at Ser637. Reason: Enzyme-substrate binding; captured by phosphatase activity and protein dephosphorylation. Supporting Evidence: PMID:18838687 Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria |
| GO:0005515 protein binding | IPI PMID:11114196 Calsarcins, a novel family of sarcomeric calcineurin-binding... | REMOVE | Summary: Calsarcin-2 (MYOZ1) binds calcineurin; calsarcins tether calcineurin to alpha-actinin at the Z-disc. Reason: Anchoring-partner binding; Z disc localization is annotated separately. Generic protein binding uninformative. Supporting Evidence: PMID:11114196 calsarcins, which tether calcineurin to alpha-actinin at the z-line of the sarcomere of cardiac and skeletal muscle cells |
| GO:0005515 protein binding | IPI PMID:11842093 Calsarcin-3, a novel skeletal muscle-specific member of the ... | REMOVE | Summary: Calsarcin-3 (MYOZ3) interacts with calcineurin. Reason: Anchoring-partner binding; generic protein binding uninformative. Supporting Evidence: PMID:11842093 Like calsarcin-1 and calsarcin-2, calsarcin-3 interacts with calcineurin, and the Z-disc proteins alpha-actinin, gamma-filamin, and telethonin. |
| GO:0006470 protein dephosphorylation | NAS PMID:8392375 Molecular cloning of a full-length cDNA encoding the catalyt... | ACCEPT | Summary: PPP3CA dephosphorylates protein substrates including NFAT, Elk-1, DNM1L Ser637, SSH1L and KLHL3 Ser433. Reason: Direct biochemical output of the catalytic activity; acceptable process term. Supporting Evidence: PMID:8392375 A complementary DNA for human calcineurin A alpha (protein phosphatase-2B), encoding a protein of 521 amino acids, was isolated from a hippocampus library. PMID:18838687 Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria PMID:15671020 calcineurin dephosphorylated SSH1L and increased the cofilin-phosphatase activity of SSH1L in cell-free assays PMID:30718414 We report herein that calcineurin normally dephosphorylates KLHL3S433-P and that this action is inhibited by CNIs |
| GO:0004722 protein serine/threonine phosphatase activity | NAS PMID:8392375 Molecular cloning of a full-length cDNA encoding the catalyt... | ACCEPT | Summary: Protein serine/threonine phosphatase activity is correct for PPP3CA (EC 3.1.3.16); direct dephosphorylation of serine/threonine sites in NFAT, Elk-1, KLHL3 Ser433 and SSH1L is documented. Reason: Correct parent of the more specific calmodulin-dependent protein phosphatase activity (GO:0033192); acceptable as stated. Supporting Evidence: PMID:8392375 A complementary DNA for human calcineurin A alpha (protein phosphatase-2B), encoding a protein of 521 amino acids, was isolated from a hippocampus library. PMID:19154138 CaN alpha dephosphorylates the transcription factor Elk-1 with 7- and 2-fold higher catalytic efficiencies than the beta and gamma isoforms, respectively PMID:30718414 We report herein that calcineurin normally dephosphorylates KLHL3S433-P and that this action is inhibited by CNIs |
| GO:0005509 calcium ion binding | NAS PMID:8392375 Molecular cloning of a full-length cDNA encoding the catalyt... | MARK AS OVER ANNOTATED | Summary: Calcium ion binding (NAS) on the catalytic subunit. The cited cloning paper does not address Ca2+ binding; CnA's metal centre is Fe3+/Zn2+, and the Ca2+-sensing EF-hands are on calcineurin B (PPP3R1) and calmodulin. Reason: Non-experimental assertion that attributes the Ca2+-binding of the regulatory subunit and calmodulin to the catalytic subunit. Kept as over-annotated rather than removed, for consistency with the PPP3CB review; CnA is Ca2+-regulated but its Ca2+ sites are on CnB. Supporting Evidence: PMID:8524402 In the native CaN structure, an auto-inhibitory element binds at the Zn/Fe-containing active site. |
| GO:0005516 calmodulin binding | NAS PMID:8392375 Molecular cloning of a full-length cDNA encoding the catalyt... | ACCEPT | Summary: PPP3CA binds Ca2+/calmodulin through the calmodulin-binding domain in its regulatory region; crystal structures of calmodulin with the CnA CaM-binding domain peptide and biophysical work on the regulatory domain show that this binding removes the autoinhibitory domain from the active site. Reason: Calmodulin binding is the activating input of calcineurin A and is directly shown with CnA peptides and the regulatory domain. Retained as a core MF that complements the catalytic activity. Supporting Evidence: PMID:8392375 A complementary DNA for human calcineurin A alpha (protein phosphatase-2B), encoding a protein of 521 amino acids, was isolated from a hippocampus library. PMID:18384083 Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. PMID:24191726 CaM binds CaN's regulatory domain (RD) and causes a conformational change that removes CaN's autoinhibitory domain (AID) from its catalytic site, activating CaN. |
| GO:0005955 calcineurin complex | NAS PMID:8392375 Molecular cloning of a full-length cDNA encoding the catalyt... | ACCEPT | Summary: PPP3CA is the catalytic A subunit of the calcineurin heterodimer (CnA/CnB, with PPP3R1); crystal structures of human calcineurin show the catalytic and regulatory subunits forming the composite surface recognized by immunophilin-drug complexes. Reason: Complex membership is structurally established and defines PPP3CA activity. Core cellular component, consistent with the PPP3CB and PPP3R1 reviews (GO:0005955). Supporting Evidence: PMID:8392375 A complementary DNA for human calcineurin A alpha (protein phosphatase-2B), encoding a protein of 521 amino acids, was isolated from a hippocampus library. PMID:8524402 In the native CaN structure, an auto-inhibitory element binds at the Zn/Fe-containing active site. PMID:12218175 The CyPA-CsA complex binds to a composite surface formed by the catalytic and regulatory subunits of CN PMID:12357034 We report the crystal structure of a Cyp/CsA/Cn ternary complex |
| GO:0005515 protein binding | IPI PMID:11114196 Calsarcins, a novel family of sarcomeric calcineurin-binding... | REMOVE | Summary: Calsarcin-1 (MYOZ2) binds calcineurin; calsarcins tether calcineurin to the Z-disc. Reason: Anchoring-partner binding; generic protein binding uninformative. Supporting Evidence: PMID:11114196 calsarcins, which tether calcineurin to alpha-actinin at the z-line of the sarcomere of cardiac and skeletal muscle cells |
| GO:0005515 protein binding | IPI PMID:19896943 WITHDRAWN: USP14 stabilizes calcineurin and regulates NFAT/A... | REMOVE | Summary: PPP3R1 interaction reported in a paper that has been WITHDRAWN. Reason: Source publication is withdrawn; in any case the CnA-CnB interaction is captured by calcineurin complex. 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:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: C16orf74/MICT1 yeast two-hybrid hit (HuRI). Reason: Generic protein binding of a docking partner; uninformative. |
| GO:0005515 protein binding | IPI PMID:26248042 Calcineurin Undergoes a Conformational Switch Evoked via Pep... | REMOVE | Summary: RCAN3 (calcipressin-3) binding; RCANs are endogenous PxIxIT/LxVP-containing calcineurin inhibitors. Reason: Inhibitor-docking interaction; the informative activity belongs on RCAN3 (calcineurin inhibitor), not on PPP3CA. Supporting Evidence: PMID:26248042 remodels the main regulatory site where NFATc transcription factors bind |
| GO:0005515 protein binding | IPI PMID:30611118 Mitogenic Signals Stimulate the CREB Coactivator CRTC3 throu... | REMOVE | Summary: Mouse CRTC1 associates with calcineurin; CRTCs are calcineurin substrates. Reason: Enzyme-substrate binding; uninformative as protein binding. Supporting Evidence: PMID:30611118 CRTC1 and CRTC2 associate selectively with the calcium-dependent phosphatase calcineurin |
| GO:0046983 protein dimerization activity | IPI PMID:11005320 Genetic conservation of the immunophilin-binding domains of ... | UNDECIDED | Summary: Protein dimerization activity (IPI, with PPP3CB and with PPP3CA itself) attributed to an SSCP polymorphism study; the abstract only states as background that calcineurin is an A/B heterodimer and reports no binding assay. Reason: Abstract-only, cannot verify. CnA-CnA or CnA-alpha/CnA-beta dimerization is not an established property of calcineurin; the A/B heterodimer is captured by calcineurin complex. Changed from REMOVE because the full text was not read. Supporting Evidence: PMID:11005320 Calcineurin is a dimeric protein consisting of distinct A (catalytic) and B (regulatory) subunits. |
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Download this section (compressed HTML)Q: To what extent are PPP3CA (CnA-alpha) and PPP3CB (CnA-beta) functionally redundant for NFAT dephosphorylation in human T cells, given that the alpha holoenzyme shows higher catalytic efficiency toward Elk-1 but similar NFAT kinetics in vitro (PMID:19154138)?
Q: Should the calcineurin-NFAT signaling cascade (GO:0033173) be linked to T cell receptor signaling pathway (GO:0050852) in a GO-CAM or module, so that PPP3CA is represented in TCR signaling through its NFAT phosphatase activity rather than through a direct GO:0050852 annotation?
Q: The PMID:11005320 annotations (IDA enzyme binding, IDA calmodulin binding, IMP calcineurin-mediated signaling, IPI protein dimerization) cite a short SSCP polymorphism report; can a curator with the full text confirm what experiment supports them?
Q: Is a nuclear pool of PPP3CA (Reactome CaN:CaM:NFAT nuclear translocation) supported experimentally in human cells?
Experiment: Isoform-selective knockout or degron depletion of PPP3CA versus PPP3CB in primary human CD4+ T cells, with NFATc1/NFATc2 dephosphorylation, nuclear import and IL2 expression readouts after TCR stimulation, to define isoform contributions.
Experiment: Phosphoproteomics in neurons expressing DEE-associated catalytic-domain loss-of-function versus ACCIID autoinhibitory-domain gain-of-function PPP3CA variants, to identify substrates whose dephosphorylation underlies the distinct phenotypes.
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