Structural determinants of muscle thin filament cooperativity

• Tropomyosin is the focus of a cooperative thin filament communication network.
• 3 states of activation of the thin filament are in rapid equilibrium in Ca2+.
• Ca2+-linked troponin shifts the equilibrium so myosin molecules bind to actin.
• Myosin shifts tropomyosin to an “open” position to activate the thin filament.
• Tuning tropomyosin behavior and the corresponding influence of Ca2+ and myosin defines muscle isotype cooperative activation.

End-to-end connections between adjacent tropomyosin molecules along the muscle thin filament allow long-range conformational rearrangement of the multicomponent filament structure. This process is influenced by Ca2+ and the troponin regulatory complexes, as well as by myosin crossbridge heads that bind to and activate the filament. Access of myosin crossbridges onto actin is gated by tropomyosin, and in the case of striated muscle filaments, troponin acts as a gatekeeper. The resulting tropomyosin-troponin-myosin on-off switching mechanism that controls muscle contractility is a complex cooperative and dynamic system with highly nonlinear behavior. Here, we review key information that leads us to view tropomyosin as central to the communication pathway that coordinates the multifaceted effectors that modulate and tune striated muscle contraction. We posit that an understanding of this communication pathway provides a framework for more in-depth mechanistic characterization of myopathy-associated mutational perturbations currently under investigation by many research groups.

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