Structure and function of Myosin VI

描述（由申请人提供）：VI类肌凝蛋白可能是非常规肌凝蛋白类别中最非常规的。与所有其他特征肌凝蛋白相比，它们以相反的方向（负端指向肌动蛋白丝）运输。肌球蛋白VI也有一个不寻常的和有争议的延长其短杠杆臂，以增加其步长。它通过一种未知的机制重新排列其转化器构象以实现大冲程和二聚化。肌球蛋白VI参与许多细胞功能，但对毛细胞的立体纤毛的维持和突变至关重要

DESCRIPTION (provided by applicant): Class VI myosins are perhaps the most unconventional of the unconventional myosin classes. They traffic in the reverse direction (minus end-directed on the actin filament) as compared to all other characterized myosins. Myosin VI also has an unusual and controversial extension of its short lever arm to increase its step size. It rearranges its converter conformation to achieve a large strok and dimerizes by an unknown mechanism. Myosin VI is involved in a number of cellular functions, but is essential for maintenance of the stereocilia of the hair cells and thus mutations in myosin VI can result in deafness. While it can function as a processive myosin motor, transporting cargoes in endocytosis, it also can function as a strain-dependent anchor that is involved in organizing structures such as the Golgi apparatus. Myosin VI is found as a monomer in cells, but functions optimally as a dimer. We have proposed that this is indicative of a novel form of regulation that may be shared by myosins VII and X~ namely, cargo-initiated dimerization. The aims of the study are: (1) further delineate the lever arm extension of myosin VI, the regions responsible for dimerization, and the mechanism of myosin VI gating~ (2) begin to probe structural aspects of myosins VIIa and X, which appear to be regulated in cells by cargo-initiated dimerization, as is the case for myosin VI~ (3) further characterize myosin VI mutations that result in deafness using both biochemical and optical trap assays~ and (4) use cellular assays (Caco-2 cells) and mutants to define anchoring vs. transport roles of myosin VI.