Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_530


Historical Background

In 1864, Kühne named a protein extracted from nematode muscle in high salt myosin and in 1939, Engelhardt and Ljubimowa determined that this protein possessed an ATPase activity. Later studies would determine that myosin is the major component of muscle thick filaments, and that its cyclic interactions with actin-containing thin filaments are the basis for muscle contraction. It would eventually be renamed myosin II to signify that the molecule is a dimer consisting of two polypeptide chains each with a globular head region and a long α-helical tail (Szent-Györgyi 2004). In 1969, a molecule resembling muscle myosin II was identified in slime mold, showing that myosin is a component of nonmuscle cells, too (Adelman and Taylor 1969). Subsequently, in 1973 a molecule with actin-activated ATPase activity resembling skeletal muscle myosin, although smaller in molecular weight and monomeric rather than filamentous, was isolated from Acanthamoeba and named  myosin I (Pollard and Korn 1973). This would be the first of many studies leading to the recognition that myosins constitute a large structurally and functionally diverse family of actin-associated molecular motor proteins that use the energy from ATP hydrolysis to translocate actin filaments usually toward the preferred (or pointed) end of actin filaments (the exception is myosin VI). In fact phylogenetic analyses based on the N-terminal domains of 328 organisms show that there are as many as 35 different myosin classes (Odronitz and Kollmar 2007). After myosin I and myosin II, the different classes that constitute the myosin superfamily are named in order of discovery usually with Roman numerals. The largest class is that of the single-headed class I myosins, which probably most closely resemble the first myosin I, a molecule predicted to have consisted of only a motor domain with a nucleotide-binding site and an actin-binding site. Humans express myosins I, II, III, V, VI, VII, IX, X, XV, XVI, XVIII, and XIX, and mutations in myosins are associated with diseases including cardiac hypertrophic myopathies, deafness, and blindness. As of mid-2010, representatives from only a small subset of the 35 different myosin classes have been either purified from tissues or expressed in vitro and studied with biochemical and biophysical approaches. Some have been expressed in cells exogenously and studied with cell biological methods.


In general, myosins have an N-terminal head or motor domain consisting of a nucleotide-binding site and an actin-binding site, a neck or light-chain-binding domain (LCBD), which binds calmodulin or calmodulin-like molecules, and a C-terminal tail domain, which is highly diverse among myosins and is the site of regions involved in dimerization as well as membrane and cargo binding. The crystal structures of the motor domains of several different classes of myosins have been solved beginning with that of chicken skeletal muscle myosin II and are similar consisting of four main subdomains: the upper 50 kDa domain, the lower 50 kDa domain, a 7-stranded β-sheet known as the transducer, and the converter region (Holmes 2008; Sweeney and Houdusse 2010). These subdomains are surrounded by several structural elements that coordinate communication among the subunits. The upper and lower 50 kDa domains form a cleft that opens and closes as a function of nucleotide binding. The nucleotide-binding pocket, highly conserved among myosins, kinesins, and G-proteins, comprises the purine-binding, or P, loop on one side and the switch 1/P-loop on the other side. Myosin motor domains have surface loops, including loop 1, near the nucleotide-binding region, and loop 2, near the actin-binding face, that differ in length and overall charge among myosins and when mutated affect a variety of kinetic properties. The C-terminal end of the motor domain is the converter region, which rotates 60° in response to ATP binding and attaches to the LCBD. Several classes of myosins, such as myosins III, IX, XV, XVI, XVIII, and XVa, contain an N-terminal extension, which contains, e.g., a serine/threonine kinase domain in the case of myosin III and several ankyrin repeats in the case of myosin XVI.

The LCBD is an α-helical region containing one or more repeats of ∼29 amino acids called IQ domains for the isoleucine and glutamine residues that are normally present. Myosins can have as few as one and as many as 17 IQ domains as in the case of the type 2 myosin from Phytophthora ramorum. The LCBD of myosin II binds a regulatory and essential light chain. The light chain of many myosins is the calcium-binding molecule calmodulin. The LCBD serves as a lever arm amplifying small structural changes in the motor domain. Myosin VI has a unique 53-amino-acid insert containing an unusual calmodulin-binding site between the motor domain and LCBD, which is responsible for redirecting the lever arm toward the minus end of actin resulting in the movement of myosin VI on actin in the direction opposite to that of other myosins (Bahloul et al. 2004).

The tail domains of myosins are highly variable in sequence and length and are involved in cargo and membrane binding as well as oligomerization of myosins (Mooseker and Foth 2008). As a consequence of long coiled-coil regions in their tails, myosins II associate to form bipolar filaments. Class V, VI, and X myosins dimerize to form two-headed molecules that move processively, i.e., take several steps along actin filaments without detaching, a property critical for carrying cargo long distances within the cell. In the case of myosin VI, dimerization is induced by binding to its adaptor proteins, optineurin and Dab2, following a conformational change that exposes dimerization sites within the myosin VI monomers (Phichith et al. 2009).

The tails of myosins contain different kinds of protein modules including those involved in protein–protein interactions such as SH3 (Src homology 3), MyTH4 and FERM, dilute, and PDZ-binding; and membrane-binding domains, such as PH domains. Myosins VII, X, XII, and XV are MYTH4-FERM myosins, defined by the presence in the tail of a Myosin Tail Homology 4 (MyTH4) domain followed by a band 4.1, Ezrin, Radixin, Moesin (FERM) domain. MyTH4-FERM myosins are implicated in mediating membrane-cytoskeleton interactions. The FERM domain in Drosophila myosin VIIa regulates its activity (Yang et al. 2009). In ATP, the tail of myosin VIIa is bent toward and interacts with the motor domain, but the molecule unfolds in the absence of ATP presumably as a consequence of actin binding by the FERM domain.

Biochemical and Mechanical Properties

Due to the similarity in structure of their motor domains, all myosins are Mg2+-ATPases believed to operate by a common mechanism (El-Mezgueldi and Bagshaw 2008). The interaction of myosin with nucleotide, defined in the 1970s by Bagshaw and Trentham, is described by a seven-step scheme in which ATP binding to myosin occurs in two steps as monitored by tryptophan fluorescence (a binding step and a protein conformational change) followed by reversible ATP hydrolysis. Phosphate (Pi) release and ADP release then occur sequentially, each dissociation event preceded by a protein conformational change. The release of phosphate is activated by the presence of actin. Kinetic differences among myosins are due primarily to differences in rates of Pi and ADP release.

The kinetic interaction of ATP with the mammalian class I myosins when bound to actin is biphasic consisting of both a fast phase and a slow phase. The studies suggest that vertebrate myosins I must undergo a conformational change before ADP release can occur, which is supported by cryo-electron microscopy studies showing that myosins I undergo an ADP-induced conformational change. These data coupled with those from studies done with optical-tweezers transducers showing that the mechanical interaction of myosin I with actin occurs in two parts led to the idea that myosins I are strain-sensitive and complete their cycle only when strain is reduced (Coluccio and Geeves 1999). This notion is supported by single-molecule studies in which the rate of detachment from actin of mammalian Myo1b decreases 75-fold under tension (Laakso et al. 2008). Although first detected in vertebrate myosins I as a consequence of their slow kinetics (Veigel et al. 1999), the interaction with actin in two mechanical parts has now been seen with other myosins.

The ability of myosins to bind and move cargo long distances along actin filaments is crucial for intracellular transport and certain myosins are specially adapted structurally and functionally for this role. Processivity, the ability to take several steps along actin before dissociating, is usually associated with motors that have a high duty ratio, i.e., they spend most of their time attached to actin. Myosin V moves processively along actin filaments because of its high affinity for actin, which ensures that one of its two heads stays associated with the actin filament while the other is detached so that the motor does not diffuse away. Strain on the lead head causes it to stall until the rear head can detach from actin. Processivity of myosin V is also supported by its long LCBD, which allows the heads to bind actin at 36 nm intervals so that the molecule can walk along the longitudinal axis of the actin filament without the viscous drag that would occur if it had to spiral around the filament (Sellers et al. 2008). Myosin VI also moves processively (although in the opposite direction), but its step size varies from 25 to 36 nm, and although it carries cargo along the longitudinal axis of the actin filament like myosin V, it can move on a right-handed spiral (Sun et al. 2007).

Single-headed myosins are non-processive motors, which make only one interaction with actin, then detach. In general these myosins have low duty ratios. Clustering of single-headed myosins could make them act as processive motors. Curiously, although Myo9B is monomeric, it can take multiple steps along actin before dissociating; the mechanism is currently unknown (Bähler 2008).


Myosins can be regulated by phosphorylation of either the heavy or light chain. Regulation of class I myosins is varied; however, phosphorylation of a single serine or threonine between the ATP- and actin-binding sites in the heavy chain of the Acanthamoeba and Dictyostelium myosins I regulates their actin-activated Mg2+-ATPase activity and motor activity. Phosphorylation by the myosin I heavy chain kinase, MIHCK, which is a p21-activated kinase (PAK), enhances the ATPase activity 40–80-fold (Brzeska and Korn 1996). In vertebrate myosins I, negatively charged glutamate or aspartate is present at the corresponding site, known as the TEDS site after the one-letter codes for the amino acids found at the site, indicating that they are constitutively active (Bement and Mooseker 1995).

The actin-activated Mg2+-ATPase activities of smooth and nonmuscle class II myosins are regulated by phosphorylation of Ser19 of the regulatory light chain, which causes unfolding of the molecule. Autophosphorylation of class III myosins leads to a decrease in the affinity for actin (Kambara et al. 2006).

Calcium plays a role in the regulation of some myosins. Although the actin-activated Mg2+-ATPase activity is higher in calcium versus EGTA, the rate of actin translocation by vertebrate myosins I is less in buffers containing calcium (Coluccio 2008). This inhibition is reversed in the presence of exogenous calmodulin, suggesting that calcium causes calmodulin dissociation from the LCBD thereby compromising its function as a lever arm. In the case of Myo1c, calmodulin dissociation might reveal sites that are then available to interact with receptors on hair cells on the sensory epithelia of the inner ear (Cyr et al. 2002). Calcium indirectly regulates myosin II activity in skeletal muscle by binding to the thin filament-associated protein, troponin, which causes a conformational change in a second thin filament-associated protein, tropomyosin, which shifts position thereby exposing sights on the thin filaments to which myosin heads can bind. The conformation of myosin V in vitro is affected by calcium with it adopting an extended form in calcium, and a folded form in buffers containing no calcium (Wang et al. 2004).


The large number of myosin classes present in eukaryotes correlates with tremendous diversity in cellular function including maintenance of cortical tension, intracellular transport, the extension of actin-containing membrane structures, and cell movement. Class I myosins in single-cell organisms contribute to pseudopod formation, motility, pinocytosis, membrane ruffling, endocytosis, secretion, and cortical tension. In vertebrates, myosins I maintain cortical tension and play specialized roles such as supporting the structure and function of intestinal microvilli, supporting adaptation in hair cells of the inner ear, and mediating the transport of GLUT4-containing vesicles in adipocytes (Coluccio 2008). Membrane tension has been shown to increase in cells overexpressing class I myosins (Nambiar et al. 2009). In skeletal and smooth muscle, myosin II-containing thick filaments slide relative to actin-containing thin filaments to effect muscle contraction (Cremo and Hartshorne 2008, Reggiani and Bottinelli 2008). In Dictyostelium amoebae, myosin II is required for cytokinesis, and cells in which expression of myosin II is knocked out cease dividing and become multinucleate (Knecht and Loomis 1987). In mice, each of the three nonmuscle myosin II isoforms is critical to normal organ development (Conti et al. 2008).  Myosin III is expressed primarily in sensory cells including the stereocilia of the hair cells of the inner ear. In hair cells, myosin III transports espin 1 to the tips of stereocilia and supports their elongation (Salles et al. 2009). Class V myosins, found in many different organisms, bind various types of cargo through their tail domains, including melanosomes, endoplasmic reticulum, and secretory vesicles and carry them long distances within cells (Sellers et al. 2008). Mutations in myosin V give rise to mutant coat colors in mice because the transport of melanosomes in melanocytes is compromised. In humans, the neurological disease, Griscelli’s Syndrome, is associated with mutations in myosin V. The plant-specific class XI myosins, responsible for intracellular transport in characean algae, are similar to that of class V myosins and translocate actin in vitro at speeds of ∼40–60 μm/s (Ito et al. 2007). Class VI myosins are found in membrane ruffles, at the Golgi and in endocytic and exocytic vesicles (Buss and Kendrick-Jones 2008). Multiple binding partners for myosin VI have been identified suggesting that it plays a variety of cellular roles. Snell’s Waltzer mice, which lack functional myosin VI, are deaf. In the hair cells of the sensory epithelium of the inner ear, myosin VI is located at the base of stereocilia where it may play a role in assembling and anchoring the stereocilia. Myosin VII is widely expressed, but most of what is known about its cellular role centers on its location in vertebrates in the hair cells of the inner ear, where it is found in both the cell body and the hair bundle; and in the retina, where it is found in the retinal pigment epithelium and rod and cone photoreceptors cells. In humans, mutations in the myosin VII gene cause Usher syndrome type 1, characterized by profound congenital deafness, vestibular dysfunction, and retinitis pigmentosis leading to blindness. Roles for myosin VII in both maintenance of tension and transportation of cargo have been suggested (El-Amraoui et al. 2008). The class IX myosins in vertebrates, Myo9a and Myo9b, are Rho GTPase-activating proteins, which are negative regulators of Rho signaling. In melanoma cells, Myo9b accumulates in lamellipodia, membrane ruffles, and filopodia. Myo9b might control actin polymerization induced by the Rho proteins, cdc42 and Rac, to prevent undesired cell extension (Bähler 2008).  Myosin X, found at the tips of filopodia, binds and transports VASP, which mediates actin assembly along filopodia, and there is a correlation between the length of filopodia and the concentration of VASP and myoX at the tips (Tokuo and Ikebe 2004). Like myosins I, III, VI, and VII, the class XV myosin, myosin XVa, is important in hearing (Boger et al. 2008). In the shaker-2 mouse, a missense mutation in myosin XVa causes deafness and circling behavior. Myosin XVa binds and transfers the scaffolding protein, whirlin, to the tips of stereocilia and is responsible for elongation of hair bundles on the sensory epithelia of the inner ear.


Myosins are a large and diverse group of actin-associated molecular motor proteins that participate in cytoskeletal functions in nearly all cells.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Boston Biomedical Research InstituteWatertownUSA