Ca²⁺/S100 regulation of giant protein kinases

Protein phosphorylation by protein kinases plays a central regulatory role in cellular processes and these kinases are themselves tightly regulated. One common mechanism of regulation involves Ca²⁺-binding proteins (CaBP) such as calmodulin (CaM). Here we report a Ca²⁺-effector mechanism for protein kinase activation by demonstrating the specific and > 1,000-fold activation of the myosin associated giant protein kinase twitchin by Ca²⁺/S100A1₂. S100A1₂ is a member of a large CaBP family that is implicated in various cellular processes, including cell growth, differentiation and motility, but whose molecular actions are largely unknown. The S100A1₂ binding site is a part of the autoregulatory sequence positioned in the active site that is responsible for intrasteric autoinhibition of twitchin kinase; the mechanism of autoinhibition based on the crystal structures of two twitchin kinase fragments is described elsewhere. Ca²⁺/S100 represents a likely physiological activator for the entire family of giant protein kinases involved in muscle contractions and cytoskeletal structure.