MyoAssemble

For proper functioning of the cell, the cytoskeleton must be continuously constructed and maintained with high fidelity. This requires the ballet of many different proteins, particularly myosin motors and their actin tracks. One such myosin, Myo18 is known to interact with the proto-typical force producing myosin, Myo2, within stress fibres during migration and muscle sarcomeres. This interaction occurs through a conserved coiled-coil domain allowing for the formation of filaments displaying arrays of active motor heads. Myo18 itself has been shown to have very little motor activity. Yet, it still binds the actin track and is heavily implicated in the proper construction of muscle tissue and cell migration. Despite tantalizing data on Myo18, a structural and mechanistic connection has not been made between the divergent activity of Myo18 and its important cellular roles. This research project aims to bridge this gap and understand the function of Myo18, and in turn how it can modulate the function of Myo2 within mixed filaments. Our consortium will integrate data from the atomic to the cellular scale through structural, biochemical, biophysical and cell biology approaches. Firstly, we aim to elucidate the nature of the interaction between Myo18 and actin. Secondly, we aim to directly assay the interaction between Myo18 and Myo2 from a structural perspective (i.e. how Myo18 can intercalate into large Myo2 architectures) and then how the inclusion of Myo18 can modulate the function of Myo2 filaments in vitro and in vivo. A holistic view upon such a divergent myosin opens new doors onto the changes in enzymatic function of myosins upon mutation and the complex sociology between myosins required for the high-fidelity construction of intricate cytoskeletal architectures.