The characterization of myosin VI has generated a number of paradigm shifting concepts leading to the proposal that a subset of myosin classes form folded, inactive monomers until binding partner engagement induces activation. This binding additionally triggers dimerization (i.e. cargo-initiated dimerization) for at least three classes of myosin (VI, VIIA, and X), which are the focus of this proposal. While folding forms the basis of regulation of two-headed myosins from class II and V, the novel form of regulation found in class VI, VIIA, and X myosins can allow these myosins to diffuse throughout the cell as compact, folded monomers until they encounter their binding partners. Since most of the cellular functions served by these myosins are at the cell periphery, either in the cortical actin or in actin extensions, this may allow efficient delivery through dense actin networks. Two of the classes appear to be optimized for movement on bundles of actin (VIIA and X), while myosin VI traffics optimally on single actin filaments. Our most recent results suggest that all three classes share another feature, namely an anti-parallel coiled coil, which has not been described in any other myosin classes. This places the heads of the dimer in a geometry that may optimize their trafficking. We will probe the key features of these myosin classes with a combination of kinetic, single molecule, structural, and cell biological studies. In addition to sharing a common form of regulation, both class VI and VIIA myosins are involved in the assembly and maintenance of strereocilia of the cochlear hair cells. Mutations in these myosins lead to deafness. We will initiate the development of molecules that may be able to counter the impact of some of these deafness mutations.
Myosin VI is the only myosin that moves in the reverse direction on actin filaments, and thus it plays unique roles in mammalian cells. One of those roles is in assembly and maintenance of stereocilia in hair cells, which are sensory receptors of both the auditory system and the vestibular system. Mutations in myosin VI lead to deafness in humans, as do mutations in myosin VIIA. We are studying the basic design of myosin VI and myosin VIIA, as well as the impact of mutations that lead to deafness, with the long-term goal of developing therapies to prevent deafness resulting from myosin VI and myosin VIIA mutations.
| Blanc, Florian; Isabet, Tatiana; Benisty, Hannah et al. (2018) An intermediate along the recovery stroke of myosin VI revealed by X-ray crystallography and molecular dynamics. Proc Natl Acad Sci U S A 115:6213-6218 |
| Wulf, Sarah F; Ropars, Virginie; Fujita-Becker, Setsuko et al. (2016) Force-producing ADP state of myosin bound to actin. Proc Natl Acad Sci U S A 113:E1844-52 |
| Ropars, Virginie; Yang, Zhaohui; Isabet, Tatiana et al. (2016) The myosin X motor is optimized for movement on actin bundles. Nat Commun 7:12456 |
| Houdusse, Anne; Sweeney, H Lee (2016) How Myosin Generates Force on Actin Filaments. Trends Biochem Sci 41:989-997 |
| Llinas, Paola; Isabet, Tatiana; Song, Lin et al. (2015) How actin initiates the motor activity of Myosin. Dev Cell 33:401-12 |
| Pylypenko, Olena; Song, Lin; Shima, Ai et al. (2015) Myosin VI deafness mutation prevents the initiation of processive runs on actin. Proc Natl Acad Sci U S A 112:E1201-9 |
| Mukherjea, Monalisa; Ali, M Yusuf; Kikuti, Carlos et al. (2014) Myosin VI must dimerize and deploy its unusual lever arm in order to perform its cellular roles. Cell Rep 8:1522-32 |
| Nelson, Michael D; Rader, Florian; Tang, Xiu et al. (2014) PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy. Neurology 82:2085-91 |
| Ali, M Yusuf; Previs, Samantha B; Trybus, Kathleen M et al. (2013) Myosin VI has a one track mind versus myosin Va when moving on actin bundles or at an intersection. Traffic 14:70-81 |
| Menetrey, Julie; Isabet, Tatiana; Ropars, Virginie et al. (2012) Processive steps in the reverse direction require uncoupling of the lead head lever arm of myosin VI. Mol Cell 48:75-86 |
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