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+/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.
Heierhorst
J
J
St. Vincent's Institute of Medical Research, Victoria, Australia.
Kobe
B
B
Feil
S C
SC
Parker
M W
MW
Benian
G M
GM
Weiss
K R
KR
Kemp
B E
BE
D000595:Amino Acid Sequence; D000818:Animals; D001048:Aplysia; D001665:Binding Sites; D029742:Caenorhabditis elegans Proteins; D002118:Calcium / Q000378:metabolism*; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D064211:Connectin; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D009418:S100 Proteins / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D002148:Calmodulin-Binding Proteins; D064211:Connectin; D009124:Muscle Proteins; D047428:Protein Kinase Inhibitors; D009418:S100 Proteins; C577285:TTN protein, human; C489233:unc-22 protein, C elegans; D011494:Protein Kinases; D002118:Calcium