Activation of calmodulin-dependent enzymes can be selectively inhibited by histone H1.
Calmodulin (CaM) and its target enzymes are important regulators of a variety of cellular processes including gene expression and cell cycle progression (Bading, H., Ginty, D. D., and Greenberg, M. E. (1993) Science 260, 181-186; Rasmussen, C. D., and Means, A. R. (1989) EMBO J. 8, 73-82). It has been previously accepted that regulation of CaM-dependent enzyme activity occurs via calcium/calmodulin-dependent activation. We have found that histone H1 is a potent inhibitor of the CaM-dependent activation of mouse calcium/calmodulin-dependent protein kinase II (CaMKII) and of the CaM-dependent protein phosphatase, calcineurin. Inhibition is mediated only by free histone H1; addition of DNA abolishes the inhibitory effect. The effect is not due to a simple interaction of basic (histone) and acidic (CaM) proteins since myelin basic protein and histone H2B, CaMKII substrates more basic than histone H1, did not affect autophosphorylation of CaMKII, and myelin basic protein had no effect on calcineurin activity. The effect is specific to CaM since addition of parvalbumin, a related Ca(2+)-binding protein, did not reverse the effect of histone H1, whereas addition of CaM recovered enzyme activity. These results indicate that free histone H1 levels may specifically affect the ability of CaM to activate its target enzymes and suggests a novel level of control of CaM-dependent enzymes in eukaryotic cells.
Rasmussen
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Department of Anatomy and Cell Biology, University of Alberta, Edmonton, Canada.
Garen
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D000818:Animals; D019703:Calcineurin; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism*; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation; D006657:Histones / Q000502:physiology*; D051379:Mice; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation
D002147:Calmodulin; D002148:Calmodulin-Binding Proteins; D006657:Histones; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D002118:Calcium