Dual-specificity phosphatase

 

This is a dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins. It also acts as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring from phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3,4-diphosphate, phosphatidylinositol 3-phosphate and inositol 1,3,4,5-tetrakisphosphate with order of substrate preference in vitro PtdIns(3,4,5)P3 > PtdIns(3,4)P2 > PtdIns3P > Ins(1,3,4,5)P4. The lipid phosphatase activity is critical for its tumor suppressor function. Its peptide phosphatase activity requires highly acidic substrates.

 

Reference Protein and Structure

Sequence
P60484 UniProt (3.1.3.16, 3.1.3.48, 3.1.3.67) IPR017361 (Sequence Homologues) (PDB Homologues)
Biological species
Homo sapiens (Human) Uniprot
PDB
1d5r - Crystal Structure of the PTEN Tumor Suppressor (2.1 Å) PDBe PDBsum 1d5r
Catalytic CATH Domains
3.90.190.10 CATHdb (see all for 1d5r)
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

The mechanism of PTEN is similar to that of protein tyrosine phosphatase 1B. Cys124 functions as a nucleophile, accepting the phosphate moiety from the phosphorylated amino acid and generating a phosphocysteine intermediate. Asp92 serves as an acid to protonate the hydroxyl oxygen atom of the leaving group. Next, the phosphate moiety is transferred to a water molecule, restoring the enzyme. Arg130 stabilises the transition state.

Catalytic Residues Roles

UniProt PDB* (1d5r)
Asp92 Asp92(86)A Serves as an acid to protonate the hydroxyl oxygen atom of the leaving group. proton shuttle (general acid/base)
Cys124 Cys124(118)A Acts as a nucleophile, accepting the phosphate moiety from the phosphorylated amino acid and generating a phosphocysteine intermediate. covalent catalysis
Arg130 Arg130(124)A Stabilises the transition state. transition state stabiliser
*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. Xiao Y et al. (2007), Cell Signal, 19, 1434-1445. PTEN catalysis of phospholipid dephosphorylation reaction follows a two-step mechanism in which the conserved aspartate-92 does not function as the general acid — Mechanistic analysis of a familial Cowden disease-associated PTEN mutation. DOI:10.1016/j.cellsig.2007.01.021. PMID:17324556.
  2. Masson GR et al. (2016), Biochem J, 473, 135-144. The intrinsically disordered tails of PTEN and PTEN-L have distinct roles in regulating substrate specificity and membrane activity. DOI:10.1042/bj20150931. PMID:26527737.
  3. Rodríguez-Escudero I et al. (2011), Hum Mol Genet, 20, 4132-4142. A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes. DOI:10.1093/hmg/ddr337. PMID:21828076.
  4. Lee JO et al. (1999), Cell, 99, 323-334. Crystal Structure of the PTEN Tumor Suppressor. DOI:10.1016/s0092-8674(00)81663-3. PMID:10555148.
  5. Maehama T et al. (1998), J Biol Chem, 273, 13375-13378. The Tumor Suppressor, PTEN/MMAC1, Dephosphorylates the Lipid Second Messenger, Phosphatidylinositol 3,4,5-Trisphosphate. DOI:10.1074/jbc.273.22.13375. PMID:9593664.

Step 1.

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Catalytic Residues Roles

Residue Roles
Asp92(86)A proton shuttle (general acid/base)
Arg130(124)A transition state stabiliser
Cys124(118)A covalent catalysis

Chemical Components

Step 1.

Contributors

Gemma L. Holliday, Mei Leung