The myosin superfamily at a glance

Abstract

The cytoskeleton is an interconnected network that provides support and organization to cells. In eukaryotes, its main components include actin and microtubules, two types of dynamic filaments. In addition to carrying out structural roles, these filaments act as tracks for the movement of molecular motors that convert chemical energy into mechanical work as they transport and/or anchor organelles, vesicles and other intracellular components. Kinesin and dynein motors both utilize microtubules for transport, whereas myosins – which are the focus of this Cell Science at a Glance article – are the only known actin-based motor proteins (Goode et al., 2000; Hartman et al., 2011; Ross et al., 2008). Different members of the myosin family are typically denoted by roman numerals, such as myosin II and myosin V; to ensure consistency between the accompanying poster and the text, we refer to them here as M2 (or class 2) and M5 (or class 5), respectively.The myosin superfamily is a large and diverse protein family, and its members, which are grouped into many classes (Foth et al., 2006; Odronitz and Kollmar, 2007), are involved in a number of cellular pathways (Krendel and Mooseker, 2005; Woolner and Bement, 2009). We first describe the basics of myosin mechanoenzymology and motility. Next, we discuss myosin–cargo interactions and present a summary of the roles of myosin proteins in cells, focusing on actin-based projections and the endomembrane system. Finally, we provide an overview of the diseases associated with myosin mutations and our perspective on the future of the myosin field. In order to provide a general overview of the myosin family, we will not be able to discuss some aspects of the vast and important literature on myosins. For example, we will not focus on the large body of literature on yeast myosins, as it deserves a rather long review on its own.Myosins contain actin- and ATP-binding sites in their conserved catalytic head domains. Conformational changes associated with nucleotide binding, hydrolysis and product release are crucial for the productive motility of myosin enzymes. In the absence of nucleotide and in the ADP-bound state, the head interacts strongly with actin. By contrast, when ATP or ADP bound to inorganic phosphate (ADP-Pi) bind to the catalytic domain, the affinity of the myosin head for actin is drastically lower. Thus, association of myosin with its filamentous track is regulated by the ATPase cycle. Myosins vary in the rate at which they use ATP and in how long per ATPase cycle they are in the strongly bound state (duty ratio). Some motor proteins, such as M2, have low duty ratios, and each myosin head spends little time in association with actin. Others, such as M5, move processively for many steps before detaching – a characteristic that results from a high duty ratio (Howard, 1997).Muscle and non-muscle M2, both of which are the conventional members of the myosin superfamily, form bipolar filaments that consist of dozens of myosin molecules. M5 and other unconventional myosins do not form such bipolar thick filaments. Some unconventional myosins, such as M5, have two heads and can take many steps along an actin filament as a single molecule. In these cases, the ATPase cycles of the two identical heads are staggered, such that at least one head is strongly bound to actin at any time. Following the binding of ATP, the rear head dissociates from the filament, which allows the front head to undergo a lever arm swing, thereby propelling the rear head forward. After the hydrolysis of ATP and the release of phosphate, the former rear head attaches to actin in its new front position (De La Cruz and Ostap, 2004).The changes in nucleotide state are associated with large movements, such as the 36-nm step taken by M5. These movements are enabled by the myosin lever arm, which amplifies the conformational changes in the catalytic domain to generate step sizes that directly depend on the length of the lever arm. In most myosins, the lever arm is a region of the heavy chain to which one or more calmodulin or calmodulin-like light chains bind and provide rigidity. In other members of the myosin family, such as M6 and M10, a single α-helix domain in this neck region may also contribute to the step size (Baboolal et al., 2009; Knight et al., 2005; Spudich and Sivaramakrishnan, 2010).The first myosin, M2, was discovered 1864 – in Heidelberg by Willy Kühne – in muscle extracts (Kühne, 1864). We now know how this muscle M2, which is localized in the so-called muscle A-bands, works. The conventional class 2 myosins have long coiled-coil domains that allow multimerization to take place. Thus, interactions between charged residues within these dimers mediate the formation of bipolar thick filaments that are responsible for contraction of muscle and cytokinesis. Each bipolar thick filament consists of dozens of myosin molecules that face opposite directions from the midzone of the filament. In muscle, t