Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
Gene Ontology annotation based on curation of immunofluorescence data
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
Cloning of human calcineurin A: evidence for two isozymes and identification of a polyproline structural domain.
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First cloning of human calcineurin A beta (PPP3CB). Identified two isozymes from alternative splicing with a unique polyproline N-terminal domain proposed to play a role in calmodulin activation.
"calcineurin A consists of at least two isozymes that may result from alternative splicing events... A role in the calmodulin activation of calcineurin is proposed for this novel structural element"
Molecular cloning of a full-length cDNA encoding the catalytic subunit of human calmodulin-dependent protein phosphatase (calcineurin A alpha).
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Full-length cDNA cloning of calcineurin A alpha. Confirms calcineurin as a calmodulin-dependent protein Ser/Thr phosphatase.
"Molecular cloning of a full-length cDNA encoding the catalytic subunit of human calmodulin-dependent protein phosphatase (calcineurin A alpha)."
Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex.
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First crystal structures of human calcineurin at 2.1 A and FKBP12-FK506-calcineurin complex at 3.5 A. Revealed autoinhibitory element at Zn/Fe active site and catalytic mechanism.
"an auto-inhibitory element binds at the Zn/Fe-containing active site. The metal-site geometry and active-site water structure suggest a catalytic mechanism involving nucleophilic attack on the substrate phosphate by a metal-activated water molecule"
Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity.
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Demonstrated direct enzyme-substrate interaction between calcineurin and NFAT1. NFAT activation is exquisitely sensitive to calcineurin activity level.
"a direct interaction between calcineurin and NFAT1 that is consistent with a direct enzyme-substrate relation between these two proteins"
Calcineurin A alpha (PPP3CA), calcineurin A beta (PPP3CB) and calcineurin B (PPP3R1) are located on human chromosomes 4, 10q21-->q22 and 2p16-->p15 respectively.
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Chromosomal localization study. PPP3CB mapped to 10q21-q22. Not a functional study.
"calcineurin A beta (PPP3CB, previous gene symbol CALNB) is present on 10q21-->q22"
Genetic conservation of the immunophilin-binding domains of human calcineurin A1 and A2.
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Immunophilin-binding domains (aa 281-414) of PPP3CA and PPP3CB are highly conserved with no polymorphisms detected.
"Single-strand conformational polymorphism (SSCP) analysis of cDNAs derived from the coding region for amino acids 281-414 of CNA1 and CNA2 in 32 healthy Caucasians did not detect polymorphic variations within these genes"
AKAP79/150 anchoring of calcineurin controls neuronal L-type Ca2+ channel activity and nuclear signaling.
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AKAP79/150 scaffolds calcineurin with PKA and L-type Ca2+ channels, enabling bidirectional regulation. Anchored CaN dominantly suppresses PKA enhancement of the channel.
"Cotargeting of PKA and CaN by AKAP79/150 confers bidirectional regulation of L-type current amplitude... anchored CaN dominantly suppresses PKA enhancement of the channel"
The proline-rich N-terminal sequence of calcineurin Abeta determines substrate binding.
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CaN beta has the lowest Km for all protein substrates, indicating highest substrate affinity. The proline-rich N-terminal sequence is involved in substrate recognition.
"CaN beta exhibits for all tested protein substrates the lowest K(m) values... the proline-rich sequence of CaN beta is involved in substrate recognition"
ANXA7, PPP3CB, DNAJC9, and ZMYND17 genes at chromosome 10q22 associated with the subgroup of schizophrenia with deficits in attention and executive function.
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GWAS association of PPP3CB locus with schizophrenia subgroup. Reduced PPP3CB mRNA expression found. Genetic association, not direct functional evidence.
"there was significantly lower expression of ANXA7, PPP3CB, and DNAJC9"
Mapping a dynamic innate immunity protein interaction network regulating type I interferon production.
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High-throughput interaction mapping. PPP3CB identified as a node in the innate immunity interactome.
"Fifty-eight baits were associated with 260 interacting proteins forming a human innate immunity interactome for type I interferon"
Balanced interactions of calcineurin with AKAP79 regulate Ca2+-calcineurin-NFAT signaling.
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AKAP79 anchoring site (IAIIIT) binds the same calcineurin surface as the PxIxIT recognition peptide of NFAT. Demonstrates balanced competition between scaffold and substrate.
"an IAIIIT anchoring site in human AKAP79 binds the same surface of calcineurin as the PxIxIT recognition peptide of NFAT, albeit more strongly"
Na(+)/H(+) exchanger 1 directly binds to calcineurin A and activates downstream NFAT signaling, leading to cardiomyocyte hypertrophy.
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NHE1 directly binds calcineurin A via PVITID motif and promotes CaN/NFAT signaling via increased intracellular pH in cardiomyocytes.
"Direct binding of CaN to the (715)PVITID(720) sequence of NHE1, which resembles the consensus CaN-binding motif (PXIXIT)"
Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB.
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PPP3CB identified as the key calcineurin isoform for TFEB dephosphorylation. Lysosomal Ca2+ release through MCOLN1 activates calcineurin, which dephosphorylates TFEB promoting nuclear translocation and autophagy/lysosomal biogenesis.
"The most significant hit identified by the primary screening was the calcineurin catalytic subunit isoform beta (PPP3CB; Gene ID:5532)"
Cooperative autoinhibition and multi-level activation mechanisms of calcineurin.
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Crystal structure of full-length PPP3CB at 2.23 A. Revealed novel autoinhibitory segment (AIS) in addition to AID. Challenges current activation model.
"revealed a novel autoinhibitory segment (AIS) in addition to the well-known autoinhibitory domain (AID). The AIS nestles in a hydrophobic intersubunit groove, which overlaps the recognition site for substrates"
The protein serine/threonine phosphatases PP2A, PP1 and calcineurin: A triple threat in the regulation of the neuronal cytoskeleton.
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Review discussing calcineurin's role in regulating neuronal cytoskeletal dynamics through dephosphorylation of cytoskeletal proteins.
"the assembly/disassembly and stability of these cytoskeletal networks is crucially modulated by protein phosphorylation and dephosphorylation events"
Mammalian Atg8 proteins and the autophagy factor IRGM control mTOR and TFEB at a regulatory node critical for responses to pathogens.
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IRGM directly interacts with calcineurin PPP3CB, promoting its association with TFEB and TFEB dephosphorylation. IRGM-dependent TFEB activation occurs during pathogen infection.
"FLAG-IRGM co-IPed with GFP-PPP3CB... A direct interaction between IRGM and PPP3CB was established in GST pull-downs... GFP-IRGM expression augmented whereas IRGM KD reduced association of TFEB with PPP3CB"
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
SPATA33 localizes calcineurin to the mitochondria and regulates sperm motility in mice.
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SPATA33 interacts with calcineurin via PQIIIT motif. Primarily relevant to sperm calcineurin (PPP3CC/PPP3R2), not PPP3CB.
"SPATA33 interacts with sperm calcineurin via a PQIIIT sequence"
Chr21 protein-protein interactions: enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer's disease.
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High-throughput Chr21 protein interaction study. PPP3CB identified as an interactor.
"Chr21 protein-protein interactions: enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer's disease"
Multimodal cell maps as a foundation for structural and functional genomics.
Calcineurin binds NFATC1,2,3
Calcineurin binds and dephosphorylates NFAT
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Calcineurin dephosphorylates NFAT, enabling nuclear translocation.
"these serine residues are dephosphorylated by calcineurin, that thought to cause exposure of nuclear localization signal sequences triggering translocation of the dephosphorylated NFAT-CaN complex to the nucleus"
Translocation of CaN:CaM:NFAT to nucleus
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Calcineurin:calmodulin:NFAT complex translocates to the nucleus.
"Dephosphorylated NFAT-calcineurin (CaN) complex translocates to nucleus, where it activates transcription of several cytokine genes"
Activation of Calcineurin
Calcineurin binds and dephosphorylates NFAT1 in response to WNT/Ca2+ signaling
Translocation of NFATC1:CaN:CaM to nucleus
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NFATC1:calcineurin:calmodulin complex translocates to the nucleus.
"Dephosphorylated NFAT-calcineurin (CaN) complex translocates to nucleus, where it activates transcription"