Module 5: Figure tyrosine phosphatase catalysis
The catalytic mechanism of protein tyrosine phosphatases.
The signature motif, located at the bottom of a deep catalytic cleft, contains three important residues (cysteine, aspartate and glycine) that are necessary for the catalytic process. A. The peptide containing the phosphotyrosine (pTyr) residue enters the cleft where the cysteine residue initiates a nucleophilic attack. The aspartate residue has a critical role in protonating the phenolate leaving group in the substrate. B. Once the phosphate has been transferred to the cysteinyl group, the substrate leaves the enzyme, and the final step is to hydrolyse the phosphate. The co-ordination of a water molecule to the glycine residue favours the hydrolysis of the phosphoryl residue. The nucleophilicity of the water molecule is increased by the abstraction of a proton by the aspartate residue. Once the phosphate has been removed, the active site is ready to hydrolyse another phosphotyrosine residue. Reproduced from Pannifer, A.D.B., Flint, A.J., Tonks, N.K. and Barford, D. (1998) Visualisation of the cysteinyl-phosphate intermediate of a protein-tyrosine phosphatase by X-ray crystallography. J. Biol. Chem. 273:10454–10462, with permission from the American Society for Biochemistry and Molecular Biology; see Pannifer et al. 1998.