Abstract
Simple SummaryAlthough actin is a highly conserved protein, it is involved in many diverse cellular processes. Actin owes its diversity of function to its ability to bind to a host of actin-binding proteins (ABPs) that localize across its surface. Among the most studied ABPs is the molecular motor, myosin. Myosin generates force on actin filaments by pairing ATP hydrolysis, product release, and actin-binding to the conformational changes that lead to movement. Central to this process is the progression of myosin binding to the actin surface as it moves through its ATPase cycle. During binding, actin acts as a myosin ATPase activator, catalyzing essential hydrolysis release steps. Here, we use the current model of actin-myosin binding as a roadmap to describe the portions of the actin-myosin interface that are sequentially formed throughout the motor cycle. At each step, we compare the interactions of a diverse set of high-resolution actin-myosin cryo-electron microscopy structures to define what portions of the interface are conserved and which are isoform-specific.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.
Highlights
Introduction to Myosin Structure myosin motors translocate along F-actin with different speeds and forces, the basic unit of the molecule is conserved and well described [59,60]
Throughout the ATPase cycle, the actin surface defines how myosin progresses from the weak binding pre-powerstroke state (PPS) to the rigor complex
Actin acts as a myosin ATPase activator, pairing sequential actin-myosin binding with ATP hydrolysis and product release
Summary
A second hydrophobic patch sometimes referred to as a groove, appears at the junction between intrastrand subunits comprised of residues M44 and M47 from the DNase-binding loop (D-loop) (see Figure 1B) and residues Y143, L349, I345, and I341 from the subdomain 1 and 3 of the minus end side of an adjacent subunit [25] This hydrophobic patch plays an important role in actin polymerization, acts as a target for post-translational modifications (PTMs), and is a locus for the binding of ABPs (see Supplementary Item Table S1) [26,27,28,29]. Several other ABPs, such as N-terminal domains of myosin binding protein C, myosin light chain kinase, and tropomyosin, do not bind to the aforementioned hydrophobic junction between actin subunits [44,45,46,47]. The topology of the actin filament and its dynamic interaction with myosin is central to the timing of these critical steps that lead to actomyosin force and motion generation
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