Structural basis for the catalytic activity of human serine/threonine protein phosphatase-5

Abstract

Serine/threonine protein phosphatase-5 (PP5) affects many signaling networks that regulate cell growth and cellular responses to stress. Here we report the crystal structure of the PP5 catalytic domain (PP5c) at a resolution of 1.6 Å. From this structure we propose a mechanism for PP5-mediated hydrolysis of phosphoprotein substrates, which requires the precise positioning of two metal ions within a conserved Asp271-M1:M 2-W1-His427-His304-Asp 274 catalytic motif (where M1 and M2 are metals and W1 is a water molecule). The structure of PP5c provides a structural basis for explaining the exceptional catalytic proficiency of protein phosphatases, which are among the most powerful known catalysts. Resolution of the entire C terminus revealed a novel subdomain, and the structure of the PP5c should also aid development of type-specific inhibitors.