Protein phosphatase 3 catalytic subunit alpha

UniProt Q08209 Organism Homo sapiens Gene CALNA, CNA, PPP3CA EC 3.1.3.16

Also known as: CALNA, CNA, PPP3CA

Function

Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals. Many of the substrates contain a PxIxIT motif and/or a LxVP motif. In response to increased Ca(2+) levels, dephosphorylates and activates phosphatase SSH1 which results in cofilin dephosphorylation. In response to increased Ca(2+) levels following mitochondrial depolarization, dephosphorylates DNM1L inducing DNM1L translocation to the mitochondrion. Positively regulates the CACNA1B/CAV2.2-mediated Ca(2+) release probability at hippocampal neuronal soma and synaptic terminals (By similarity). Dephosphorylates heat shock protein HSPB1 (By similarity). Dephosphorylates and activates transcription factor NFATC1. In response to increased Ca(2+) levels, regulates NFAT-mediated transcription probably by dephosphorylating NFAT and promoting its nuclear translocation. Dephosphorylates and inactivates transcription factor ELK1. Dephosphorylates DARPP32. May dephosphorylate CRTC2 at 'Ser-171' resulting in CRTC2 dissociation from 14-3-3 proteins. Dephosphorylates transcription factor TFEB at 'Ser-211' following Coxsackievirus B3 infection, promoting nuclear translocation. Required for postnatal development of the nephrogenic zone and superficial glomeruli in the kidneys, cell cycle homeostasis in the nephrogenic zone, and ultimately normal kidney function (By similarity). Plays a role in intracellular AQP2 processing and localization to the apical membrane in the kidney, may thereby be required for efficient kidney filtration (By similarity). Required for secretion of salivary enzymes amylase, peroxidase, lysozyme and sialic acid via formation of secretory vesicles in the submandibular glands (By similarity). Required for calcineurin activity and homosynaptic depotentiation in the hippocampus (By similarity). Required for normal differentiation and survival of keratinocytes and therefore required for epidermis superstructure formation (By similarity). Positively regulates osteoblastic bone formation, via promotion of osteoblast differentiation (By similarity). Positively regulates osteoclast differentiation, potentially via NFATC1 signaling (By similarity). May play a role in skeletal muscle fiber type specification, potentially via NFATC1 signaling (By similarity). Negatively regulates MAP3K14/NIK signaling via inhibition of nuclear translocation of the transcription factors RELA and RELB (By similarity). Required for antigen-specific T-cell proliferation response (By similarity). Dephosphorylates KLHL3, promoting the interaction between KLHL3 and WNK4 and subsequent degradation of WNK4. Negatively regulates SLC9A1 activity.

Classification

Family (Pfam): PF00149 Metallophos
InterPro: Calcineurin-like_PHP, Metallo-depent_PP-like, MPP_PP2B, PP2B, Ser/Thr-sp_prot-phosphatase
Functional cluster: Mixed Regulatory & Membrane Proteins

Experimental structures · PDB · 21

1AUI X-ray 2.10A
1M63 X-ray 2.80A
1MF8 X-ray 3.10A
2JOG NMR
2JZI NMR
2P6B X-ray 2.30A
2R28 X-ray 1.86A
2W73 X-ray 1.45A
3LL8 X-ray 2.00A
4F0Z X-ray 1.70A
4Q5U X-ray 1.95A
5C1V X-ray 3.35A
… and 9 more

A predicted model is available from AlphaFold.

Gene Ontology · 53

Disease associations

developmental and epileptic encephalopathy 91 MONDO:0020630
arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development MONDO:0032642

Drugs targeting this protein · 1

VOCLOSPORIN inhibitor

Related proteins · sequence + function similarity

Co-cited proteins · studied together in the literature

Calcineurin subunit B type 1 10 shared papers
Uncharacterized protein C16orf74 1 shared papers
Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform 2 shared papers
IkB-like protein 1 shared papers
Calcipressin-3 1 shared papers
Protein phosphatase Slingshot homolog 1 1 shared papers
Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform 2 shared papers
Kelch-like protein 3 1 shared papers
Peptidyl-prolyl cis-trans isomerase A 2 shared papers
A-kinase anchor protein 6 1 shared papers
Synaptopodin-2 1 shared papers
Dynamin-1-like protein 1 shared papers

Literature · 41 cited papers

SPATA33 localizes calcineurin to the mitochondria and regulates sperm motility in mice. Proc. Natl. Acad. Sci. U.S.A. · 2021
Coxsackievirus B3 targets TFEB to disrupt lysosomal function. Autophagy · 2021
Molecular basis for the binding and selective dephosphorylation of Na+/H+ exchanger 1 by calcineurin. Nat. Commun. · 2019
Calcineurin dephosphorylates Kelch-like 3, reversing phosphorylation by angiotensin II and regulating renal electrolyte handling. Proc. Natl. Acad. Sci. U.S.A. · 2019
Mitogenic Signals Stimulate the CREB Coactivator CRTC3 through PP2A Recruitment. IScience · 2018
Novel calcineurin A (PPP3CA) variant associated with epilepsy, constitutive enzyme activation and downregulation of protein expression. Eur. J. Hum. Genet. · 2019
Loss-of-function and gain-of-function mutations in PPP3CA cause two distinct disorders. Hum. Mol. Genet. · 2018
A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis. Elife · 2017
De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures. Am. J. Hum. Genet. · 2017
Overexpression of C16orf74 is involved in aggressive pancreatic cancers. Oncotarget · 2017
Investigating the human Calcineurin Interaction Network using the piLxVP SLiM. Sci. Rep. · 2016
Calcineurin Undergoes a Conformational Switch Evoked via Peptidyl-Prolyl Isomerization. PLoS ONE · 2015
… and 29 more in the literature graph

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