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Ca²⁺ and Ionic Strength Dependencies of S1-ADP Binding to Actin-Tropomyosin-Troponin: Regulatory Implications

Boris Gafurov , Yi-Der Chen ^* and Joseph M. Chalovich 

^*Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-5621; and Department of Biochemistry and Molecular Biology, Brody School of Medicine at East Carolina University, Greenville, North Carolina 27858-4354

Correspondence: Address reprint requests to Joseph M. Chalovich, Dept. of Biochemistry and Molecular Biology, Brody School of Medicine at East Carolina University, 600 Moye Blvd., Greenville, North Carolina, 27834. Tel.: 252-744-2973; Fax: 252-744-3383; E-mail: chalovichj{at}mail.ecu.edu.

Skeletal and cardiac muscle contraction are inhibited by the actin-associated complex of tropomyosin-troponin. Binding of Ca²⁺ to troponin or binding of ATP-free myosin to actin reverses this inhibition. Ca²⁺ and ATP-free myosin stabilize different tropomyosin-actin structural arrangements. The position of tropomyosin on actin affects the binding of ATP-free myosin to actin but does not greatly affect myosin-ATP binding. Ca²⁺ and ATP-free myosin alter both the affinity of ATP-free myosin for actin and the kinetics of that binding. A parallel pathway model of regulation simulated the effects of Ca²⁺ and ATP-free myosin binding on both equilibrium binding of myosin-nucleotide complexes to actin and the general features of ATPase activity. That model was recently shown to simulate the kinetics of myosin-S1 binding but the analysis was limited to a single condition because of the limited data available. We have now measured equilibrium binding and binding kinetics of myosin-S1-ADP to actin at a series of ionic strengths and free Ca²⁺ concentrations. The parallel pathway model of regulation is consistent with those data. In that model the interaction between adjacent regulatory complexes fully saturated with Ca²⁺ was destabilized and the inactive state of actin was stabilized at high ionic strength. These changes explain the previously observed change in binding kinetics with increasing ionic strength.

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