Study of Cell Adhesion Through an Analysis of Myosin 7

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Myosin VII (M7) is an actin-based motor protein known to play an essential role in hearing and balance in humans, mice and zebrafish. The simple eukaryote Dictyostelium expresses a M7 homologue (DdM7) and null mutant analysis has revealed that it plays a critical role in cell substrate adhesion required for phagocytosis and cell migration, a novel function for a myosin. Emerging evidence from mammalian systems is consistent with M7's direct involve involvement in adhesion, indicating that the role of this class of myosins has been conserved throughout evolution. Our analysis of Ddm7 suggests that this myosin plays a role in organizing receptors into a high affinity complex (the adhesion complex) that is capable of binding to surfaces and is not involved in the transport of proteins to the plasma membrane. Furthermore, we have found that the tail region of Ddm7 is essential for the formation of this adhesion complex. The goal of our work is to identify the molecular basis of DdM7-based adhesion by answering the following major questions: 1) What are the proteins that link DdM7 to the adhesion complex? Both biochemical and genetic approaches will be used to identify proteins that bind to DdM7 and participate in cell adhesion; and 2) How do the linker proteins interact with DdM7 to make an adhesion complex. A complementation analysis will be employed to identify regions of the DdM7 molecule required for linking this myosin to the adhesion complex. Given the conservation of M7 function throughout evolution, the detailed molecular analysis of M7 function in a genetically tractable system such as Dictyostelium shall offer a unique opportunity to gain insight into how M7-based adhesion functions in the specialized cells of the auditory and vestibular system and how mutations in M7, such as occur in Usher's syndrome type IB, might lead to deafness.