MYO10
Myosin X, also known as MYO10, is a protein that in humans is encoded by the MYO10 gene.
Myo10 is an actin-based motor protein that can localize to the tips of the finger-like cellular protrusions known as filopodia. Myo10 is broadly expressed in mammalian tissues, although at relatively low levels. Studies with knockout mice demonstrate that Myo10 has important functions in embryonic processes such as neural tube closure and eye development. Myo10 also has important functions in cancer invasion and growth.
Myo10 should not be confused with Myh10, which encodes the heavy chain of the class II myosin known as non-muscle myosin 2b.
Structure and function
The human MYO10 gene spans ~274 kb and is located on chromosome 5 band 5p15.1. It produces a full-length RNA transcript with 41 exons encoding a MYO10 heavy chain whose deduced sequence has 2058 amino acids and a predicted molecular weight of ~237 kDa. Like many motor proteins, the full-length Myo10 protein can be considered to consist of a head, neck, and tail. The N-terminal head or myosin motor domain can bind to an actin filament, hydrolyze ATP, and produce force. The neck or light chain binding domain consists of 3 IQ motifs, with each IQ motif providing a binding site for one molecule of calmodulin, a ~16.5 kDa calcium-binding protein. Unlike most calmodulin binding sites, which only bind to calmodulin in the presence of calcium, the IQ motifs in Myo10 can bind to calmodulin in the absence of calcium. The Myo10 IQ motifs have also been reported to bind CALML3, a calmodulin-like protein expressed in epithelial cells, so CALML3 may serve as a Myo10 light chain in place of calmodulin in some situations. The Myo10 tail begins with an alpha-helical region whose proximal portion forms a single, stable alpha helix that lengthens the lever arm formed by the neck domain. The distal portion of the alpha helical region can self-associate with a Kd of ~0.6 uM to form an antiparallel coiled coil, allowing two Myo10 heavy chains to form an antiparallel dimer, a unique structure among known myosins.The Myo10 tail includes several regions in addition to the SAH and coiled coil. These include a region with 3 PEST sequences—sequences enriched in the amino acids Proline, Glutamine, Serine, and T that are often associated with cleavage by proteases such as calpain. The Myo10 tail is unique among known myosins in containing 3 PH domains, a domain often involved in binding to membranes. The sequence of Myo10's first PH domain is somewhat unusual in that it is split by the presence of a surface loop that contains the second PH domain. The second PH domain binds to the important signaling lipid phosphatidylinositol (3,4,5)-trisphosphate and in some situations has been reported to bind to phosphatidylinositol (4,5)-bisphosphate . Myo10's 3 PH domains are thought to work together to recruit it to the plasma membrane. The Myo10 tail ends in a supramodule consisting of a MyTH4 domain and a FERM domain. Myo10's MyTH4 domain can bind to microtubules with a reported affinity of ~0.24 uM and gives full-length Myo10 the important ability to link an actin filament bound by its head to a microtubule bound by its tail. The Myo10 FERM domain can bind to the cytoplasmic domains of several β-integrins, a major class of cell adhesion receptor, and to the cytoplasmic domains of the netrin receptors Deleted in Colorectal Cancer and neogenin. Although full-length Myo10 protein appears to be expressed at relatively low levels, it can be detected in most mammalian tissues including brain, testes, kidney, lung, stomach, and pancreas.
The native full-length Myo10 heavy chain can exist as a monomer with 3 calmodulin/calmodulin-like light chains or as an antiparallel dimer with 6 calmodulin/calmodulin-like light chains. An antiparallel Myo10 dimer with all 6 light chains would thus have 8 subunits and a native MW of ~574 kDa. Importantly, the tail in a Myo10 monomer can fold back onto the head to inhibit the head's motor activity. Increases in plasma membrane PIP3 levels are hypothesized to recruit Myo10 monomers to the plasma membrane via their PH domains, activating their motor activity and increasing their local concentration, leading to the formation of active antiparallel dimers that are capable moving along actin filaments. Myo10, like all known myosins other than Myo6, moves towards the barbed end of the actin filament. Myo10 is capable of hydrolyzing ~10-20 ATP/s per head and has been reported to generate movement at rates of ~300-1500 nm/s. Single-molecule studies show that native Myo10 dimers can take steps of up to ~55 nm, which are among the largest steps reported for a motor protein. Myo10's large step size is due in part to the long lever arm formed by its neck domain and stable alpha helix, and in part due to the remarkably large swing of ~120° the Myo10 lever arm undergoes during its power stroke. There is much interest in the mechanisms that target Myo10 to filopodial actin bundles, and in Myo10's ability to step from one actin filament in a bundle to another. In addition to the full-length Myo10 described above, the use of alternative transcription start sites located in intron 19-20 of the full-length transcript results in the production of "headless" Myo10 transcripts that lack most of the myosin head domain, but include the rest of the Myo10 heavy chain. The major headless transcripts in human are predicted to include exons 20-41 of full-length MYO10 and initiation of translation at M644 would result in a 1415 amino acid headless protein with a predicted MW of ~163 kDa that would be identical to amino acids 644-2058 of full-length MYO10. Because headless Myo10 lacks most of the head domain, it lacks motor activity, but it retains all of Myo10's other domains and is thus expected to retain the ability to bind to light chains of the calmodulin superfamily, to membranes containing PIP3 or PIP3, to microtubules, and to proteins that bind the Myo10 tail such as DCC, neogenin, and β-integrins. Headless Myo10 has been hypothesized to act as a scaffolding protein for its various binding partners and/or as a "natural" dominant negative that can inhibit the actions of full-length Myo10.