Kinesin and its relatives are microtubule motors that generate intracellular movements by converting the chemical energy in ATP into force and movement. While much is known about the organization of these motors and their potential functions, many holes in our knowledge remain. In particular, we do not understand how the mechanochemical transduction of ATP occurs, nor do we fully understand how kinesin motors are regulated and function in the cell. The goal of the work described in this proposal is to elucidate these issues by achieving several interrelated goals. First, to expand our understanding of mechanochemical force transduction, we will obtain high- quality crystals of the kinesin motor domain and solve its atomic structure. Second, in complementary analyses of the kinesin motor, we will identify regions involved in binding to the microtubule, and sequences important in mechanochemistry. Third, to broaden our understanding of kinesin regulation and function, we will focus on genetic and biochemical analysis of proteins that interact at the kinesin tail, in particular on the kinesin light chains and kinectin, which may be regulatory or attachment proteins involved in kinesin function. Fourth, to extend our knowledge of the mechanisms of axonal transport and the roles played by kinesin motors, we will genetically analyze the functions of KLP64D and KLP68D, which are two kinesin relatives that are very likely to function in anterograde axonal transport along with kinesin. Taken together, our studies should significantly advance our understanding of the functions, and mechanisms of function, of kinesin and its relatives.
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