Ca2+ /S100 regulation of giant protein kinases

• DOI: 10.1038/380636a0
• Publication Date: 2003-08-12T01:59:53Z
• Authors: Jörg Heierhorst; Bostjan Kobe; Susanne C. Feil; Michael W. Parker; Guy M. Benian; Klaudiusz R. Weiss; Bruce E. Kemp
• Keywords: Models, Molecular; 0301 basic medicine; 571; Binding Sites; Protein Conformation; Molecular Sequence Data; S100 Proteins; Muscle Proteins; Crystallography, X-Ray; 060111 Signal Transduction; Multidisciplinary Sciences; Enzyme Activation; 03 medical and health sciences; Aplysia; Science & Technology - Other Topics; Animals; Humans; Calcium; Calmodulin-Binding Proteins; Connectin; Amino Acid Sequence; Caenorhabditis elegans Proteins; Protein Kinase Inhibitors; 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+/S100A1(2). S100A1(2) 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 S100A1(2)-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.