The Central Role of the F-Actin Surface in Myosin Force Generation

Abstract

Actin is one of the most abundant and versatile proteins in eukaryotic cells. As discussed in many contributions to this Special Issue, its transition from a monomeric G-actin to a filamentous F-actin form plays a critical role in a variety of cellular processes, including control of cell shape and cell motility. Once polymerized from G-actin, F-actin forms the central core of muscle-thin filaments and acts as molecular tracks for myosin-based motor activity. The ATP-dependent cross-bridge cycle of myosin attachment and detachment drives the sliding of myosin thick filaments past thin filaments in muscle and the translocation of cargo in somatic cells. The variation in actin function is dependent on the variation in muscle and non-muscle myosin isoform behavior as well as interactions with a plethora of additional actin-binding proteins. Extensive work has been devoted to defining the kinetics of actin-based force generation powered by the ATPase activity of myosin. In addition, over the past decade, cryo-electron microscopy has revealed the atomic-evel details of the binding of myosin isoforms on the F-actin surface. Most accounts of the structural interactions between myosin and actin are described from the perspective of the myosin molecule. Here, we discuss myosin-binding to actin as viewed from the actin surface. We then describe conserved structural features of actin required for the binding of all or most myosin isoforms while also noting specific interactions unique to myosin isoforms.

Conformational changes linked to ADP release from human cardiac myosin bound to actin-tropomyosin

“…In both structures, the cleft separating upper and lower 50K domains is closed and the helix-loop-helix motif and cardiomyopathy loop tether the motor to the actin filament mainly via hydrophobic contacts. The myosin surface loops 2, 3, 4, and the activation loop form a secondary interface, without significant differences from previous work (Doran and Lehman, 2021). The conservation of the actomyosin interface in the ADP-bound and rigor states coincides with actin-binding affinity measurements, which report that both states bind to F-actin with nanomolar affinities (Yengo et al, 2002).…”

Structural Mechanisms of Actin Isoforms

“…The myosin enzymatic cycle can be categorized into states with weak (ATP, ADP·Pi) and strong (ADP, nucleotide-free (apo)) actin affinity (51, 52). In the strong affinity states, a binding interface is established between actin and the myosin motor domain (18, 53, 54). To determine whether myosin binding to actin modulates actin filament structure, we compared the structures of filamentous bare actin isoforms with previous high-resolution cryo-EM structures of myosin-bound actins.…”

Integrating comparative modeling and accelerated simulations reveals conformational and energetic basis of actomyosin force generation

“…4,5 The physical properties of the cycle are tuned to accomplish a variety of cellular tasks for different myosin isoforms. 6,7 In muscle, the basic contractile apparatus is formed primarily by myosin (thick) and actin (thin) filaments, which slide past each other to contract the muscle fiber. 8 The interaction between myosin head and actin powered by ATP results in the cross-bridge formation.…”

“…formation of a tight myosin-actin interface, actin-binding cleft closure, lever arm swing, and ATP hydrolysis products (phosphate and ADP) release. Despite extensive structural, biochemical, and single-molecule studies (see reviews 7,19,20 ), the causality and ordering of these events are difficult to characterize. Recent cryo-EM structures provide atomistic views of different myosin-actin isoforms at the strongly bound rigor state, [21][22][23][24] in which no nucleotide is bound to the active site.…”

“…4,5 The physical properties of the cycle are tuned to accomplish a variety of cellular tasks for different myosin isoforms. 6,7…”