Regulation of myosin VI motor activity by cargo binding in vivo and in vitro

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The biological cell resembles a very busy miniature factory with a large collection of dedicated protein machines working together to maintain the health and welfare of the cell. These machines have highly specific functions and are driven by chemical energy to perform a variety of different tasks. One example are the highly specialized motor proteins that can move along filament tracks in a step-by-step motion powered by the chemical energy derived from ATP hydrolysis. These motor proteins move cargo around the cell to specific locations rather like a train running along a railway network to its specific destination. There are 3 types of motors that work on either large microtubule bundles or actin filament networks, which spread like spider's webs all over the cell. Our research focuses on the molecular motor protein myosin 6, which is unique, because it is the only myosin motor that comes with a reverse gear and therefore can move in the opposite direction to all the other molecular motors along actin filaments. The cargo is hooked up to this motor with the help of a large number of specific adaptor proteins that we have recently identified. The aim of our research is to determine how the specific cargo molecules are selected and attached to the motor and how this triggers the motor to start to move to its destinations in the cell. In addition it is important to understand how this molecular machine is controlled and regulated by identifying its on/off switches, since defects in myosin 6 can cause a number of diseases including deafness and also potentially Alzheimer's disease and prostate cancer. We thus intend to identify the mechanisms that regulate myosin 6 and its adaptor proteins for the transport of cargo to specific regions of the cell. This work will open up new areas of research that will guide future clinical studies and the development of potential diagnostic tools and possible therapeutic strategies to treat dementia and cancer.