カルモジュリン依存性ホスファターゼ
Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform
EC=3.1.3.16
Alternative name(s):
CAM-PRP catalytic subunit
Calmodulin-dependent calcineurin A subunit alpha isoform
Gene names
Name: PPP3CA
Synonyms: CALNA, CNA
Function
Calcium-dependent, calmodulin-stimulated protein phosphatase. Many of the substrates contain a PxIxIT motif. This subunit may have a role in the calmodulin activation of calcineurin. Dephosphorylates DNM1L, HSPB1 and SSH1. Ref.12 Ref.13 Ref.17
Catalytic activity
[a protein]-serine/threonine phosphate + H2O = [a protein]-serine/threonine + phosphate.
Cofactor
Binds 1 Fe3+ ion per subunit.
Binds 1 zinc ion per subunit.
Subunit structure
Interacts with CIB1; the interaction increases upon cardiomyocytes hypertrophy By similarity. Interacts with CHP1 and CHP2 By similarity. Composed of two components (A and B), the A component is the catalytic subunit and the B component confers calcium sensitivity. Interacts with CRTC2, MYOZ1, MYOZ2 and MYOZ3. Interacts with DNM1L; the interaction dephosphorylates DNM1L and regulates its translocation to mitochondria. Interacts with CMYA5; this interaction represses calcineurin activity in muscle By similarity. Ref.9 Ref.10 Ref.11 Ref.13
Subcellular location
Cell membrane By similarity. Cell membrane › sarcolemma By similarity. Nucleus By similarity. Note: Colocalizes with ACTN1 and MYOZ2 at the Z line in heart and skeletal muscle By similarity.
Sequence similarities
Belongs to the PPP phosphatase family. PP-2B subfamily.
Regions
Region 2 – 301 300 Catalytic
Region 247 – 253 7 Calcineurin B binding-site 1 Potential
Region 296 – 301 6 Calcineurin B binding-site 2 Potential
Region 392 – 414 23 Calmodulin-binding Potential
Region 465 – 487 23 Inhibitory domain
Serine/threonine-protein phosphatase 5
Short name=PP5
EC=3.1.3.16
Alternative name(s):
Protein phosphatase T
Short name=PP-T
Short name=PPT
Gene names
Name: PPP5C
Synonyms: PPP5
Function
Serine/threonine-protein phosphatase that dephosphorylates a myriad of proteins involved in different signaling pathways including the kinases CSNK1E, ASK1/MAP3K5, PRKDC and RAF1, the nuclear receptors NR3C1, PPARG, ESR1 and ESR2, SMAD proteins and TAU/MAPT. Implicated in wide ranging cellular processes, including apoptosis, differentiation, DNA damage response, cell survival, regulation of ion channels or circadian rhythms, in response to steroid and thyroid hormones, calcium, fatty acids, TGF-beta as well as oxidative and genotoxic stresses. Participates in the control of DNA damage response mechanisms such as checkpoint activation and DNA damage repair through, for instance, the regulation ATM/ATR-signaling and dephosphorylation of PRKDC and TP53BP1. Inhibits ASK1/MAP3K5-mediated apoptosis induced by oxidative stress. Plays a positive role in adipogenesis, mainly through the dephosphorylation and activation of PPARG transactivation function. Also dephosphorylates and inhibits the anti-adipogenic effect of NR3C1. Regulates the circadian rhythms, through the dephosphorylation and activation of CSNK1E. May modulate TGF-beta signaling pathway by the regulation of SMAD3 phosphorylation and protein expression levels. Dephosphorylates and may play a role in the regulation of TAU/MAPT. Through their dephosphorylation, may play a role in the regulation of ions channels such as KCNH2. Ref.8 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.19 Ref.21 Ref.23 Ref.24 Ref.25 Ref.26
Catalytic activity
[a protein]-serine/threonine phosphate + H2O = [a protein]-serine/threonine + phosphate.
Cofactor
Binds 2 divalent metal cation per subutnit.
Enzyme regulation
Autoinhibited. The TPR domain, unique in that protein family, engage to form an extensive interface with the catalytic region preventig access of the substrate to the catalytic pocket. Allosterically activated by various polyunsaturated fatty acids, free long-chain fatty-acids and long-chain fatty acyl-CoA esters, arachidonic acid being the most effective activator. HSP90A and probably RAC1, GNA12 and GNA13 can also release the autoinhibition by the TPR repeat. Activation by RAC1, GNA12 and GNA13 is synergistic with the one produced by fatty acids binding. Inhibited by okadaic acid. Ref.8 Ref.13 Ref.21 Ref.25 Ref.29 Ref.31
Subunit structure
Part of a complex with HSP90/HSP90AA1 and steroid receptors. Interacts with CDC16, CDC27. Interacts with KLHDC10 (via the 6 Kelch repeats); inhibits the phosphatase activity on MAP3K5. Interacts (via TPR repeats) with HSP90AA1 (via TPR repeat-binding motif) or HSPA1A/HSPA1B; the interaction is direct and activates the phosphatase activity. Dissociates from HSPA1A/HSPA1B and HSP90AA1 in response to arachidonic acid. Interacts with ATM and ATR; both interactions are induced by DNA damage and enhance ATM and ATR kinase activity. Interacts with RAD17; reduced by DNA damage. Interacts with nuclear receptors such as NR3C1/GCR and PPARG (activated by agonist); regulates their transactivation activities. Interacts (via TPR repeats) with S100 proteins S100A1, S100A2, S100A6, S100B and S100P; the interactions are calcium-dependent, strongly activate PPP5C phosphatase activity and compete with HSP90AA1 and MAP3K5 interactions. Interacts with SMAD2 and SMAD3 but not with SMAD1; decreases SMAD3 phosphorylation and protein levels. Interacts (via TPR repeats) with CRY1 and CRY2; the interaction with CRY2 downregulates the phosphatase activity on CSNK1E. Interacts (via TPR repeats) with the active form of RAC1, GNA12 or GNA13; these interactions activate the phosphatase activity and translocate PPP5C to the cell membrane. Ref.9 Ref.10 Ref.13 Ref.17 Ref.21 Ref.24 Ref.25 Ref.26 Ref.29 Ref.30
Subcellular location
Nucleus. Cytoplasm. Membrane. Note: Predominantly nuclear. But also present in the cytoplasm. Ref.13 Ref.21 Ref.24
Tissue specificity
Ubiquitous. Ref.14
Post-translational modification
Activated by at least two different proteolytic cleavages producing a 56 kDa and a 50 kDa form.
Sequence similarities
Belongs to the PPP phosphatase family. PP-5 (PP-T) subfamily.
Contains 3 TPR repeats.
Biophysicochemical properties
Kinetic parameters:
KM=1.847 µM for CSNK1E (at 30 degrees Celsius) Ref.14 Ref.17
KM=13.2 µM for MAPT/TAU (at pH 7.4 and 30 degrees Celsius)
