Structure and Function of Myosin VI

摘要/摘要： 肌球蛋白VI的特征已经产生了许多范式转变的概念，导致了 建议肌球蛋白类别的子集形成折叠的、不活跃的单体，直到结合伙伴参与 诱导激活。这种结合另外触发二聚化(即，货物引发的二聚化)至少 三类肌球蛋白(VI、VIIA和X)，这是本提案的重点。虽然折叠构成了 调节第II类和第V类的双头肌球蛋白，这是在第VI类、第VIIA类和第VI类中发现的一种新的调节形式 X肌球蛋白可以使这些肌球蛋白以致密、折叠的单体在细胞内扩散，直到它们 遇到它们的绑定伙伴。因为这些肌球蛋白的大部分细胞功能都在细胞内 无论是在皮质肌动蛋白还是在肌动蛋白延伸的外围，这可能允许通过密集的肌动蛋白有效地传递 网络。其中两个类似乎针对肌动蛋白束(VIIA和X)的运动进行了优化，而 肌球蛋白VI在单个肌动蛋白细丝上的运输效果最佳。我们最新的结果表明，这三个班级 共享另一个特征，即反平行的螺旋线圈，这在任何其他肌球蛋白中都没有描述 上课。这将二聚体的头部放置在一个几何图形中，可能会优化它们的运输。我们将调查 这些肌球蛋白类别的主要特征是动力学、单分子、结构和细胞的组合 生物学研究。 除了共享一种共同的调节形式外，VI类和VIIA肌球蛋白都参与了 耳蜗毛细胞纤毛的组装和维持。这些肌球蛋白的突变导致 耳聋。我们将启动分子的开发，这些分子可能能够对抗一些 这些耳聋突变。

Summary/Abstract: 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.