|Protein name||Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform||Serine/threonine-protein phosphatase PP1-alpha catalytic subunit||Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform||Calcineurin subunit B type 1||phosphoprotein phosphataseprotein phosphatase-1protein phosphatase-2Aprotein phosphatase-2Bprotein phosphatase-2Cprotein D phosphatasephosphospectrin phosphatasecasein phosphataseAspergillus awamori acid protein phosphatasecalcineurinphosphatase 2Aphosphatase 2Bphosphatase IIphosphatase IBphosphatase C-IIpolycation modulated (PCM-) phosphatasephosphopyruvate dehydrogenase phosphatasephosphatase SPbranched-chain alpha-keto acid dehydrogenase phosphataseBCKDH phosphatase3-hydroxy 3-methylglutaryl coenzymeA reductase phosphataseHMG-CoA reductase phosphatasephosphatase H-IIphosphatase IIIphosphatase Iprotein phosphatasephosphatase IV|
|Synonyms||EC 220.127.116.11Calmodulin-dependent calcineurin A subunit alpha isoformCAM-PRP catalytic subunit||PP-1AEC 18.104.22.168||EC 22.214.171.124Calmodulin-dependent calcineurin A subunit alpha isoformCAM-PRP catalytic subunit||Protein phosphatase 2B regulatory subunit 1Protein phosphatase 3 regulatory subunit B alpha isoform 1|
|Activity||A phosphoprotein + H(2)O = a protein + phosphate.||A phosphoprotein + H(2)O = a protein + phosphate.||A phosphoprotein + H(2)O = a protein + phosphate.|
|Subunit||Composed of two components (A and B), the A component is the catalytic subunit and the B component confers calcium sensitivity. Interacts with TORC2/CRTC2, MYOZ1, MYOZ2 and MYOZ3.||PP1 comprises a catalytic subunit, PPP1CA, PPP1CB or PPP1CC, which is folded into its native form by inhibitor 2 and glycogen synthetase kinase 3, and then complexed to one or several targeting or regulatory subunits. PPP1R12A, PPP1R12B and PPP1R12C mediate binding to myosin. PPP1R3A, PPP1R3B, PPP1R3C and PPP1R3D mediate binding to glycogen. PPP1R15A and PPP1R15B mediate binding to EIF2S1. Part of a complex containing PPP1R15B, PP1 and NCK1/2. Interacts with PPP1R9A, PPP1R9B and PPP1R7 (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 TORC2/CRTC2, MYOZ1, MYOZ2 and MYOZ3 (By similarity).||Composed of a catalytic subunit (A) and a regulatory subunit (B).|
|Subcellular location||Nucleus (By similarity). Note=Colocalizes with ACTN1 and MYOZ2 at the Z line in heart and skeletal muscle (By similarity).||Cytoplasm (By similarity).||Nucleus (By similarity). Note=Colocalizes with ACTN1 and MYOZ2 at the Z line in heart and skeletal muscle (By similarity).|
|Cofactor||Binds 1 Fe(3+) ion per subunit.,Binds 1 zinc ion per subunit.||Binds 1 iron ion per subunit.,Binds 1 manganese ion per subunit.||Binds 1 Fe(3+) ion per subunit.,Binds 1 zinc ion per subunit.|
|Type||heavy metal||heavy metal||heavy metal||divalent metal (Ca2+, Mg2+)||peptide/protein||peptide/protein,phosphate group/phosphate ion||H2O||peptide/protein,phosphate group/phosphate ion||aromatic ring (only carbon atom),phosphate group/phosphate ion||amine group,phosphate group/phosphate ion||peptide/protein||phosphate group/phosphate ion|
|References for Catalytic Mechanism|
|References||Sections||No. of steps in catalysis|
|Comments||X-ray crystallography (2.1 Angstroms)|
|Authors||Griffith JP, Kim JL, Kim EE, Sintchak MD, Thomson JA, Fitzgibbon MJ, Fleming MA, Caron PR, Hsiao K, Navia MA|
|Title||X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex.|
|Comments||X-ray crystallography (2.1 Angstroms, complex with FKBP12-FK506;3.5 Angstroms)|
|Authors||Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk A, Kalish VJ, Tucker KD, Showalter RE, Moomaw EW, et al|
|Title||Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex.|
|Comments||X-ray crystallography (2.1 Angstroms)|
|Authors||Goldberg J, Huang HB, Kwon YG, Greengard P, Nairn AC, Kuriyan J|
|Title||Three-dimensional structure of the catalytic subunit of protein serine/threonine phosphatase-1.|
|Journal||Trends Biochem Sci|
|Title||Molecular mechanisms of the protein serine/threonine phosphatases.|
|Authors||Hengge AC, Martin BL|
|Title||Isotope effect studies on the calcineurin phosphoryl-transfer reaction: transition state structure and effect of calmodulin and Mn2+.|
|Authors||Rusnak F, Mertz P|
|Title||Calcineurin: form and function.|
|Journal||Proc Natl Acad Sci U S A|
|Authors||Huai Q, Kim HY, Liu Y, Zhao Y, Mondragon A, Liu JO, Ke H|
|Title||Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes.|
|In this enzyme, the dinuclear metal center (Fe/Zn or Fe/Mn) seems to play a key role in the catalysis . According to the paper , the metal coordination of the phosphate ester seems to be essential in the following functions:|
(a) lower the pKa of the metal-coordinated water molecule, in order to make the water nucleohilic.
(b) neutralize the negative charge on the oxygen atoms of the phosphate ester, in order to increase the electrophilicity of the phosphorous atom, making it more susceptible to the nucelophilic attack.
(c) orient the substrate for in-line attack.
Moreover, the redox state of the iron is also important . Fe3+ is required for the role as Lewis acid to lower the pKa of the bound water, whilst Fe2+ has a decreased Lewis acidity .
Furthermore, two arginine residues (Arg122/Arg254 for 1aui) seem to stabilize the transition state by neutralizing the negatively charged phosphate ester .
Although the paper  suggested many possible roles of His151/Asp121 (such as acid/base, substrate binding, general base, and orienting the nucleophilic hydroxide solvent molecule) in the catalysis, it proposed a dissociative (SN1-like) mechanism, where the histidine residue play a dual role as a general base and a general acid, as follows;
(1) Substrate phosphoryl group might also coordinate to one or both metal ions. The two arginine residues, Arg122/Arg254, may neutralize charge by forming hydrogen bonds with the oxygen atoms of the phosphoryl group, which make the substrate more electrophilic and ready for attack by a nucleophile.
(2) His151 acts as a general base to abstract proton from the metal-bound water molecule, or may orient the nucleophilic water for optimal nucleophilic attack of the phosphate ester.
(3) A dissociative transition state is formed, where bond cleavage to the leaving group has occurred prior to bond formation to the nucleophile.
(4) A metal-bound water hydroxide coordinated to Fe3+ acts as the attacking nucleophile, with the Fe3+ working as a Lewis acid to lower the pKa of the water.
(5) P-O bond cleavage in the transition state results in a negative charge on the leaving group, which causes neutralization of the negative charge by protonation with a general acid (His151) or by coordination to a metal ion (Zn2+). Here, the two arginine residues are also important for the transition state stabilization.
(6) The phosphate bridge the two metal ions of the dinuclear center.
(7) The phosphate is exchanged by a solvent water molecule, which regenerates the enzyme for another turnover.
On the other hand, the paper  suggested that the metal-bound water molecule acts as a nucleophile to attack the phosphorus atom of a phosphate group in an SN2 mechanism (associative mechanism).