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Effects of Actin-Myosin Kinetics on the Calcium Sensitivity of Regulated Thin Filaments
AuthorO'Donnell, Timothy James
AdvisorBaker, Jonathan E.
Biochemistry and Molecular Biology
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Activation of thin filaments in striated muscle occurs when tropomyosin exposes myosin binding sites on actin either through calcium-troponin binding or by actin-myosin (AM) strong binding. However, the extent to which each of these binding events contributes to thin filament activation remains unclear. Here we propose a simple analytical model in which strong AM binding and calcium-troponin binding independently activate the rate of AM weak-to-strong binding. The model makes clear predictions for how activation varies with pCa as well as AM attachment, N·katt, and detachment, kdet, kinetics. To test the model, we use an in vitro motility assay to measure the myosin-based sliding velocities of thin filaments at different pCa, N·katt, and kdet values. We observe that the combined effects of varying pCa, N·katt, and kdet are accurately fit by the analytical model. The model and supporting data imply that changes in attachment and detachment kinetics predictably affect the calcium sensitivity of striated muscle mechanics, providing a novel AM kinetic-based interpretation for perturbations (e.g., disease-related mutations) that alter calcium sensitivity.