Abstract
Activation of thin filaments in striated muscle occurs when tropomyosin exposes myosin binding sites on actin either through calcium-troponin (Ca-Tn) binding or by actin-myosin (A-M) strong binding. However, the extent to which these binding events contributes to thin filament activation remains unclear. Here we propose a simple analytical model in which strong A-M binding and Ca-Tn binding independently activates the rate of A-M weak-to-strong binding. The model predicts how the level of activation varies with pCa as well as A-M attachment, N·k(att), and detachment, k(det), 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·k(att), and k(det) values. We observe that the combined effects of varying pCa, N·k(att), and k(det) 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 A-M kinetic-based interpretation for perturbations (e.g. disease-related mutations) that alter calcium sensitivity.
Highlights
Activation of striated muscle is a calcium-dependent process, with initial studies describing calcium binding as a switch that can turn regulated thin filaments “on” or “off” [1, 2]
As [MgATP] is further decreased a peak velocity is reached at which point the thin filament velocity is maximally activated and exhibits a velocity consistent with that observed in the presence of saturating calcium
Model for Thin Filament Activation—The model proposed is described in terms of the mechanochemistry of myosin interactions with regulated thin filaments illustrated in Fig. 2, based on the single molecule studies of Kad et al [17]
Summary
Activation of striated muscle is a calcium-dependent process, with initial studies describing calcium binding as a switch that can turn regulated thin filaments “on” or “off” [1, 2]. We use an in vitro motility assay to determine how changing the model parameters N, katt, kdet, and pCa influences the activation level of the velocity, V, at which thin filaments slide over a bed of skeletal muscle myosin.
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