tail is unique among known myosins in containing 3 PH domains (Pleckstrin Homology domain), 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 [PI(3,4,5)P3] and in some situations has been reported to bind to phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2]. 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 (Myosin Tail Homology 4) and a FERM domain (band 4.1, Ezrin, Radixin, Moesin). 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 (DCC) and neogenin (Neo1). 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 PI(3,4,5)P3 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