Mechanisms of Processivity in Molecular Motors

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DESCRIPTION (provided by applicant): Myosins and kinesins make up a diverse collection of molecular motors that generate force and movement at the expense of nucleotide hydrolysis. Despite the fact that these two motor superfamilies share little primary structure, members of each group often serve similar functions within the cell. For example, while some myosins and kinesins transport vesicles, others generate the cortical tension required to maintain the cytoskeleton and the mitotic apparatus. The central hypothesis of this project is that the physiologic demands placed on a motor determine how it behaves as an enzyme. It should therefore be possible to predict key aspects of a motor's enzymology if its function within the cell is known. Myosin V and conventional kinesin transport vesicles relatively long distances and work as single motors in isolation. Consistent with the central hypothesis, these two motors share at least one feature of their enzymology--both are processive. Processivity would be necessary for vesicle transporters that work in isolation, since premature dissociation could have dire physiologic consequence. Thus, processivity serves as an example of how a motor's enzymology can be shaped by its physiology. In this proposal, I will expand on this theme of processivity as a response to physiologic demands. I will use the data I have generated with kinesin to formulate a model of how processivity works in molecular motors, and will test this model by comparing kinesin to myosin V. In particular, I will examine three components of molecular motor enzymology whose features should be predictable for vesicle transporters that work in isolation. These include the timing of the forward step, the flexibility of the motor's mechanical element, and the mechanism of allosteric communication. Taken together, these components are likely to determine how processive a motor is, and like processivity itself, they too should be shaped by the demands of physiology. Determining how closely these components conform to the predictions based on physiology will therefore provide a critical test of the central hypothesis. Furthermore, if successful, this work will support the argument that understanding how a motor works in vitro as an enzyme can provide valuable insights into how it works in vivo in the cell.