Key result
Accelerating ADP release in muscle myosin II requires ~0.4 kT of energy, nearly doubling release rates.
Provides a thermodynamic model and in vitro experimental evidence demonstrating that allosteric regulation of ADP release in myosin is driven primarily by intermolecular mechanical work and dissipation of interhead forces rather than active-site conformational changes alone.
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Thermodynamic model links interhead strain to ADP release in myosins; leaves open whether similar energetics govern cardiac contractility in vivo.
Myosin molecules are involved in a wide range of transport and contractile activities in cells. A single myosin head functions through its ATPase reaction as a force generator and as a mechanosensor, and when two or more myosin heads work together in moving along an actin filament, the interplay between these mechanisms contributes to collective myosin behaviors. For example, the interplay between force-generating and force-sensing mechanisms coordinates the two heads of a myosin V molecule in its hand-over-hand processive stepping along an actin filament. In muscle, it contributes to the Fenn effect and smooth muscle latch. In both examples, a key force-sensing mechanism is the regulation of ADP release via interhead forces that are generated upon actin-myosin binding. Here we present a model describing the mechanism of allosteric regulation of ADP release from myosin heads as a change, DeltaDeltaG(-D), in the standard free energy for ADP release that results from the work, Deltamicro(mech), performed by that myosin head upon ADP release, or DeltaDeltaG(-D) = Deltamicro(mech). We show that this model is consistent with previous measurements for strain-dependent kinetics of ADP release in both myosin V and muscle myosin II. The model makes explicit the energetic cost of accelerating ADP release, showing that acceleration of ADP release during myosin V processivity requires approximately 4 kT of energy whereas the energetic cost for accelerating ADP release in a myosin II-based actin motility assay is only approximately 0.4 kT. The model also predicts that the acceleration of ADP release involves a dissipation of interhead forces. To test this prediction, we use an in vitro motility assay to show that the acceleration of ADP release from both smooth and skeletal muscle myosin II correlates with a decrease in interhead force. Our analyses provide clear energetic constraints for models of the allosteric regulation of ADP release and provide novel, testable insights into muscle and myosin V function.
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Jackson et al. (2009) studied Allosteric regulation of ADP release from myosin heads. ATP concentration variation (0.007 to 1 mM ATP) and interhead mechanical strain in an in vitro actin motility assay vs. Low ATP concentrations (<100 µM) vs high ATP concentrations (>100 µM) or absence of myosin was evaluated on Strain-dependent ADP release rates (k-D) and energetic cost of accelerating ADP release (ΔΔG-D = Δμmech). Accelerating ADP release requires ~4 kT of energy in myosin V versus ~0.35-0.4 kT in muscle myosin II, doubling ADP release rates from 55 to 96 s⁻¹ in smooth and 174 to 291 s⁻¹ in skeletal myosin.
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