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PPP3CA

OverviewProducts

Domain

The autoinhibitory domain prevents access to the catalytic site.

The autoinhibitory segment prevents access to the substrate binding site.

Possible isomerization of Pro-309 within the SAPNY motif triggers a conformation switch which affects the organization and thus accessibility of the active site and the substrate binding region (PxIxIF motif). The trans- to cis-transition may favor calcineurin A activation and substrate binding. The reverse cis- to trans-transition may be enhanced by peptidyl-prolyl isomerases such as PPIA.

Function

Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals (PubMed:15671020, PubMed:18838687, PubMed:19154138, PubMed:23468591). Many of the substrates contain a PxIxIT motif and/or a LxVP motif (PubMed:17498738, PubMed:17502104, PubMed:23468591, PubMed:27974827, PubMed:22343722). In response to increased Ca(2+) levels, dephosphorylates and activates phosphatase SSH1 which results in cofilin dephosphorylation (PubMed:15671020). In response to increased Ca(2+) levels following mitochondrial depolarization, dephosphorylates DNM1L inducing DNM1L translocation to the mitochondrion (PubMed:18838687). Dephosphorylates heat shock protein HSPB1 (By similarity). Dephosphorylates and activates transcription factor NFATC1 (PubMed:19154138). In response to increased Ca(2+) levels, regulates NFAT-mediated transcription probably by dephosphorylating NFAT and promoting its nuclear translocation (PubMed:26248042). Dephosphorylates and inactivates transcription factor ELK1 (PubMed:19154138). Dephosphorylates DARPP32 (PubMed:19154138). May dephosphorylate CRTC2 at 'Ser-171' resulting in CRTC2 dissociation from 14-3-3 proteins (PubMed:30611118). Dephosphorylates transcription factor TFEB at 'Ser-211' following Coxsackievirus B3 infection, promoting nuclear translocation (PubMed:33691586).

Involvement in disease

Epileptic encephalopathy, infantile or early childhood, 1

IECEE1

A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. IECEE1 is an autosomal dominant condition with onset of seizures between the first weeks and first years of life.

None

The disease is caused by variants affecting the gene represented in this entry.

Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development

ACCIID

An autosomal dominant disease characterized by moderate to severe intellectual disability, craniosynostosis, cleft palate, micrognathia, arthrogryposis, and short stature. Some patients may present bone abnormalities and generalized seizures.

None

The disease is caused by variants affecting the gene represented in this entry.

Sequence similarities

Belongs to the PPP phosphatase family. PP-2B subfamily.

Tissue specificity

Expressed in keratinocytes (at protein level).

Cellular localization

  • Cytoplasm
  • Cell membrane
  • Peripheral membrane protein
  • Cell membrane
  • Sarcolemma
  • Cytoplasm
  • Myofibril
  • Sarcomere
  • Z line
  • Cell projection
  • Dendritic spine
  • Colocalizes with ACTN1 and MYOZ2 at the Z line in heart and skeletal muscle (By similarity). Recruited to the cell membrane by scaffold protein AKAP5 following L-type Ca(2+)-channel activation (PubMed:22343722).

Alternative names

  • Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform
  • CAM-PRP catalytic subunit
  • Calmodulin-dependent calcineurin A subunit alpha isoform
  • CNA
  • CALNA
  • PPP3CA

Database links

Target type

Proteins

Molecular weight

58688Da