Abstract
The motor protein myosin drives a wide range of cellular and muscular functions by generating directed movement and force, fueled through adenosine triphosphate (ATP) hydrolysis. Release of the hydrolysis product adenosine diphosphate (ADP) is a fundamental and regulatory process during force production. However, details about the molecular mechanism accompanying ADP release are scarce due to the lack of representative structures. Here we solved a novel blebbistatin-bound myosin conformation with critical structural elements in positions between the myosin pre-power stroke and rigor states. ADP in this structure is repositioned towards the surface by the phosphate-sensing P-loop, and stabilized in a partially unbound conformation via a salt-bridge between Arg131 and Glu187. A 5 Å rotation separates the mechanical converter in this conformation from the rigor position. The crystallized myosin structure thus resembles a conformation towards the end of the two-step power stroke, associated with ADP release. Computationally reconstructing ADP release from myosin by means of molecular dynamics simulations further supported the existence of an equivalent conformation along the power stroke that shows the same major characteristics in the myosin motor domain as the resolved blebbistatin-bound myosin-II·ADP crystal structure, and identified a communication hub centered on Arg232 that mediates chemomechanical energy transduction.
Highlights
IntroductionMyosin is a ubiquitously expressed adenosine triphosphate (ATP)-driven motor protein, producing force and directed motion along cytoskeletal actin filament tracks by converting chemical energy from
Myosin is a ubiquitously expressed adenosine triphosphate (ATP)-driven motor protein, producing force and directed motion along cytoskeletal actin filament tracks by converting chemical energy fromATP hydrolysis into mechanical work
Myosin is a molecular motor cycling through a series of complex conformational transitions while transforming chemical energy into mechanical work
Summary
Myosin is a ubiquitously expressed adenosine triphosphate (ATP)-driven motor protein, producing force and directed motion along cytoskeletal actin filament tracks by converting chemical energy from. A multitude of cellular processes is driven by these molecular machines, ranging from cell motility and division to cargo transport, endocytosis, and contraction of cardiac, skeletal, and smooth muscles. Despite their specialized cellular functions, all members of the myosin superfamily share a common multistep mechanism of force generation—the chemomechanical actomyosin motor cycle (Figure 1A) [1,2,3].
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