Unconventional Myosins: How Regulation Meets Function

Figures

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  Figure 1. Schematic representation of the multiple roles that unconventional myosins fulfil in key cellular processes. The myosins, whose regulation is discussed in this review, are illustrated as examples. Depending on their structural and mechano-enzymatic features, each myosin can function as a monomer or dimer and can act as a cargo transporter, molecular anchor, actin cross-linker or tension sensor. Note that each myosin can be assigned to a broad range of intracellular roles. Because of this multi-functionality, myosins require tight spatial and temporal regulation, which is achieved at multiple levels.

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  Figure 2. Schematic representation of the architecture of unconventional myosins and their various mechanisms of regulation. Myosins consist of three main regions: the highly conserved motor head domain; the neck domain which can include one to six IQ motifs, which bind calmodulin or other light chains; and the highly diverse tail domain which can include coiled-coil regions that mediate dimerization, helical lever arm extension (LAE) regions, single α-helix (SAH) regions that can also serve as lever arm extensions, and various lipid- and/or protein-binding domains that mediate the interaction of myosins with membranes and their cargo adaptors, such as pleckstrin homology (PH), Src homology 3 (SH3) domain, myosin tail homology 4–band 4.1, ezrin, radixin, moesin (MyTH4-FERM) domain, PSD95/Dlg/ZO1 (PDZ) domain, followed by a cargo binding domains (CBD) in myosin VI or globular tail domain (GTD) in myosin V. Various regulatory mechanisms are deployed in order to tune the activity, conformation, oligomeric state, intracellular localization and function of myosins. These mechanisms are depicted here in relation to the region of the myosin which gets regulated.

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  Figure 3. Regulation of myosin VI through the interplay between alternative splicing and binding partner interaction. Alternative splicing of myosin VI results in four different isoforms, including a non-insert (NI) and a large insert (LI) isoform. In the NI isoform, the two 3 amino acid partner binding motifs RRL and WWY are equally accessible. In contrast, in the LI isoform, the LI helix masks the RRL motif. The motifs are characterized by different affinities, with the RRL motif being the high affinity site. In the case of the LI isoform, alternative splicing interferes with binding partner selectivity in two ways: a) by masking the high affinity RRL site, therefore favoring interactions with the lower affinity WWY partners, like Dab2 and b) by directly enhancing the interaction with Dab2. In the case of the NI isoform, partner selectivity is dictated by the differential affinity between the two sites, hence favoring the interactions with RRL partners like NDP52. This also allows the competition between binding partners to be driven in the cell by the localized concentration of binding partners. The interaction with the selected partner triggers the conversion of each isoform from a…