PROTEIN-TYROSINE PHOSPHATASES - BIOLOGICAL FUNCTION, STRUCTURAL CHARACTERISTICS, AND MECHANISM OF CATALYSIS

The protein-tyrosine phosphatases (PTPases) superfamily consists of ty rosine-specific phosphatases, dual specificity phosphatases, and the l ow-molecular-weight phosphatases. They are modulators of signal transd uction pathways that regulate numerous cell functions. Malfunction of PTPases have been linked to a number of oncogenic and metabolic diseas e states, and PTPases are also employed by microbes and viruses for pa thogenicity. There is little sequence similarity among the three subfa milies of phosphatases. Yet, three-dimensional structural data show th at they share similar conserved structural elements, namely, the phosp hate-binding loop encompassing the PTPase signature motif (H/V)C(X)(5) R(S/T) and an essential general acid/base Asp residue on a surface loo p. Biochemical experiments demonstrate that phosphatases in the PTPase superfamily utilize a common mechanism for catalysis going through a covalent thiophosphate intermediate that involves the nucleophilic Cys residue in the PTPase signature motif, The transition states for phos phoenzyme intermediate formation and hydrolysis are dissociative in na ture and are similar to those of the solution phosphate monoester reac tions. One strategy used by these phosphatases for transition state st abilization is to neutralize the developing negative charge in the lea ving group. A conformational change that is restricted to the movement of a flexible loop occurs during the catalytic cycle of the PTPases. However, the relationship between loop dynamics and enzyme catalysis r emains to be established. The nature and identity of the rate-limiting step in the PTPase catalyzed reaction requires further investigation and may be dependent on the specific experimental conditions such as t emperature, pH, buffer, and substrate used. in-depth kinetic and struc tural analysis of a representative number of phosphatases from each gr oup of the PTPase superfamily will most likely continue to yield insig htful mechanistic information that may be applicable to the rest of th e family members.