Activation of Skeletal Muscle Myosin Light Chain Kinase by Calcium(2+) and Calmodulin

Donald K. Blumenthal, James T. Stull

Research output: Contribution to journalArticlepeer-review

208 Scopus citations


Many biological processes are now known to be regulated by Ca2+ via calmodulin (CM). Although a general mechanistic model by which Ca2+ and calmodulin modulate many of these activities has been proposed, an accurate quantitative model is not available. A detailed analysis of skeletal muscle myosin light chain kinase activation was undertaken in order to determine the stoichiometrics and equilibrium constants of Ca2+, calmodulin, and enzyme catalytic subunit in the activation process. The analysis indicates that activation is a sequential, fully reversible process requiring both Ca2+ and calmodulin. The first step of the activation process appears to require binding of Ca2+ to all four divalent metal binding sites on calmodulin to form the complex, Ca4 2+•calmodulin. This complex then interacts with the inactive catalytic subunit of the enzyme to form the active holoenzyme complex, Ca4 2+•calmodulin-enzyme. Formation of the holoenzyme follows simple hyperbolic kinetics, indicating a 1 : 1 stoichiometry of Ca4 2+•calmodulin to catalytic subunit. The rate equation derived from the mechanistic model was used to determine the values of KCa 2+ and KCM, the intrinsic activation constants for each step of the activation process. KCa 2+ and KCM were found to have values of 10 µM and 0.86 nM, respectively, at 10 mM Mg2+. The rate equation using these equilibrium constants accurately predicts the extent of enzyme activation over a wide range of Ca2+ and calmodulin concentrations. The kinetic model and analytical techniques employed herein may be generally applicable to other enzymes with similar regulatory schemes.

Original languageEnglish (US)
Pages (from-to)5608-5614
Number of pages7
Issue number24
StatePublished - Feb 1 1980

ASJC Scopus subject areas

  • Biochemistry


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