In addition to the conventional myosins (class II) required for processes such as muscle contraction and cytokinesis, the myosin superfamily of actin-based motor proteins includes at least 14 ‘unconventional’ classes. These unconventional myosins are defined by myosin-like head (motor) domains attached to class-specific tail domains that differ greatly from those of myosin-II. The unconventional myosins account for almost two-thirds of the 28 or more myosin genes currently believed to be expressed in humans and 80–90% of the ∼10 or more myosin genes expressed in a typical nonmuscle cell. Although these members of the myosin superfamily have not been as intensively investigated as the conventional myosins, unconventional myosins are known or believed to power many forms of actin-based motility and organelle trafficking. The presence of signaling domains such as kinase domains, SH3 domains, PH domains or GTPase-activating domains in the tails of unconventional myosins indicates that these proteins can also be components of signal transduction pathways. Since several classes of the myosin superfamily have been found only in lower eukaryotes or plants (VIII, XI, XIII and XIV), in this review we will focus on the structures and properties of the unconventional myosins found in multicellular animals (excluding classes I and V, which have been reviewed elsewhere recently). Special attention will be focused on the three classes of unconventional myosins that can cause deafness in mouse or humans when mutated. In addition, we discuss the discovery of a pair of intriguing domains, the Myosin Tail Homology 4 (MyTH4) and FERM (band 4.1, Ezrin, Radixin, Moesin) domains, that are present in the tails of otherwise very different myosins as well as a plant kinesin-like protein. Recent progress in the identification of novel unconventional myosins will also be summarized.
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