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, <italic>N*katt</italic>, and detachment,<italic>k<sub>det</sub></italic>, 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, <italic>N*katt</italic>, and <italic>k<sub>det</sub></italic> values. We observe that the combined effects of varying pCa, <italic>N*katt</italic>, and <italic>k<sub>det</sub></italic> 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.