Protein phosphatase 2B

 

Protein phosphatase 2B (also known as calcineurin) is a Ca(II)- and calmodulin-stimulated protein serine/threonine phosphatase. Many of the substrates contain a PxIxIT motif. This catalytic subunit (represented by UniProtKB Q08209) may have a role in the calmodulin activation of calcineurin. UniProtKB P63098 represents the regulatory subunit of calcineurin and confers calcium sensitivity.

This protein plays an important role in numerous calcium-dependent biological processes, including neurodevelopment and memory, immune response, cardiac hypertrophy, signal transduction, and muscle development.

 

Reference Protein and Structure

Sequences
Q08209 UniProt (3.1.3.16)
P63098 UniProt IPR006186 (Sequence Homologues) (PDB Homologues)
Biological species
Homo sapiens (Human) Uniprot
PDB
1aui - HUMAN CALCINEURIN HETERODIMER (2.1 Å) PDBe PDBsum 1aui
Catalytic CATH Domains
3.60.21.10 CATHdb (see all for 1aui)
Cofactors
Iron(3+) (1), Zinc(2+) (1)
Click To Show Structure

Enzyme Reaction (EC:3.1.3.16)

O-phospho-L-serine(2-) residue
CHEBI:83421ChEBI
+
water
CHEBI:15377ChEBI
→
L-serine residue
CHEBI:29999ChEBI
+
hydrogenphosphate
CHEBI:43474ChEBI
Alternative enzyme names: 3-hydroxy 3-methylglutaryl coenzymeA reductase phosphatase, Aspergillus awamori acid protein phosphatase, BCKDH phosphatase, HMG-CoA reductase phosphatase, Branched-chain alpha-keto acid dehydrogenase phosphatase, Calcineurin, Casein phosphatase, Phosphatase 2A, Phosphatase 2B, Phosphatase C-II, Phosphatase H-II, Phosphatase I, Phosphatase IB, Phosphatase II, Phosphatase III, Phosphatase IV, Phosphatase SP, Phosphopyruvate dehydrogenase phosphatase, Phosphospectrin phosphatase, Polycation modulated (PCM-) phosphatase, Protein D phosphatase, Protein phosphatase, Protein phosphatase-1, Protein phosphatase-2A, Protein phosphatase-2B, Protein phosphatase-2C, Serine/threonine specific protein phosphatase, Phosphoprotein phosphatase,

Enzyme Mechanism

Introduction

An iron-activated water molecule is deprotonated by histidine and carries out a nucleophilic attack on the substrate (a phosphorylated serine or threonine residue). The histidine then donates the proton to the amino acid leaving group.

The 'Asp-His-(OH)-Fe' tetrad is very similar to the 'Asp-His-Ser' triad of serine proteases.

Catalytic Residues Roles

UniProt PDB* (1aui)
His151 His151A General acid/base. proton shuttle (general acid/base)
Asp121 Asp121A Stabilises histidine residue when it is positively charged. electrostatic stabiliser
Arg254, Arg122 Arg254A, Arg122A Stabilises negatively charged transition state. transition state stabiliser
Asn150, His281, His199, Asp118 Asn150A, His281A, His199A, Asp118A Forms the zinc binding site. metal ligand
Asp90, His92, Asp118 Asp90A, His92A, Asp118A Forms the iron binding site metal ligand
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

References

  1. Shi Y (2009), Cell, 139, 468-484. Serine/Threonine Phosphatases: Mechanism through Structure. DOI:10.1016/j.cell.2009.10.006. PMID:19879837.
  2. Zhang M et al. (2013), FEBS J, 280, 4739-4760. Viewing serine/threonine protein phosphatases through the eyes of drug designers. DOI:10.1111/febs.12481. PMID:23937612.
  3. Li H et al. (2011), Trends Cell Biol, 21, 91-103. Interaction of calcineurin with substrates and targeting proteins. DOI:10.1016/j.tcb.2010.09.011. PMID:21115349.
  4. Rusnak F et al. (2000), Physiol Rev, 80, 1483-1521. Calcineurin: form and function. PMID:11015619.
  5. Kissinger CR et al. (1995), Nature, 378, 641-644. Crystal structures of human calcineurin and the human FKBP12–FK506–calcineurin complex. DOI:10.1038/378641a0. PMID:8524402.

Step 1.

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Catalytic Residues Roles

Residue Roles
Asp118A metal ligand
Asn150A metal ligand
His199A metal ligand
His281A metal ligand
Asp90A metal ligand
His92A metal ligand
Asp121A electrostatic stabiliser
His151A proton shuttle (general acid/base)
Arg122A transition state stabiliser
Arg254A transition state stabiliser

Chemical Components

Step 1.

Contributors

Stuart Lucas, Gemma L. Holliday