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Ca2+ /S100 regulation of giant protein kinases

Abstract

PROTEIN phosphorylation by protein kinases plays a central regulatory role in cellular processes and these kinases are themselves tightly regulated1. One common mechanism of regulation involves Ca2+-binding proteins (CaBP) such as calmodu-lin (CaM)2. 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+/S100Al2. 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 unknown3. The S100Al2-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 elsewhere4. Ca2+/S100 represents a likely physiological activator for the entire family of giant protein kinases involved in muscle contractions and cyto-skeletal structure2,5–9.

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Heierhorst, J., Kobe, B., Feil, S. et al. Ca2+ /S100 regulation of giant protein kinases. Nature 380, 636–639 (1996). https://doi.org/10.1038/380636a0

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