Chapter 109 - Protein Tyrosine Phosphatase Structure and Mechanisms

Abstract

The protein tyrosine phosphatase (PTP) family of enzymes dephosphorylate target signaling proteins and are involved in the diverse regulation of numerous cell functions. PTPs comprise a large gene-family (112 genes) with the minimal catalytic motif CX 5 R, where C is the cysteine nucleophile that attacks the phosphate group, R is the arginine residue that binds phosphate and stabilizes the transition state, and X represents any amino acid. A large subgroup of the PTPs are capable of efficient hydrolysis of both phosphotyrosine and phosphothreonine/serine residues and are often referred to as dual-specificity PTPs. Members of the PTP family can be soluble or membrane-associated proteins, as in the receptor-like PTPs. The common feature of these phosphatases appears to be the basic catalytic mechanism involving the formation of a phospho-cysteinyl enzyme intermediate, using the conserved cysteine, arginine, and general acid/base aspartate residue. The catalytic domain of PTPs consists of an α/β fold composed of a highly twisted core of β-strands flanked by α-helices. Domains outside of the catalytic fold serve as regulatory and/or targeting modules. The structure, substrate recognition, catalytic mechanism, and modes of regulation are discussed in this chapter.