Defining Effects of Myosin VII Structure and Kinetics on Hereditary Deafness

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DESCRIPTION (provided by applicant): Myosin VII belongs to the myosin family of actin-activated ATPase motor proteins responsible for generating force on the actin cytoskeleton in eukaryotes. In mammals, myosin VII is generally expressed in polarized cellular structures that form ordered arrays of actin-rich protrusions. Based on phenotypes of mutant organisms and biochemical studies demonstrating that myosin VII dwells in a state strongly-bound to actin, this myosin is thought to act primarily as an anchor by maintenance of tension between the cytoskeleton and membrane components in these structures. Mutations in myosin Vila results in one of the most common forms of inherited deafness in humans, but the molecular basis of disease presentation is currently unknown. Despite its biomedical importance, the structural and kinetic details that dictate how this motor performs its cellular functions are currently lacking. The long term goal of this proposal is to gain an understanding of the enzymatic and structural adaptations in myosin VII and how these contribute to precise biological function. Specifically, the first aim of this proposal is to identify how mutations that generate deafness phenotypes in humans disrupt the enzymatic and motor properties of myosin Vila. The second aim is to determine the oligomeric state of native myosin VII, which is necessary to develop a complete model of myosin VII function and motility in cells. As a whole, the work described in this proposal is directed towards the attainment of a more complete model for myosin VII function and will provide insight to the molecular basis of deafness that results from myosin VII dysfunction. Relevance to public health: Mutations in myosin Vila are directly associated with the development of Usher syndrome type Ib (and various other forms of inherited deafness), comprising one of the largest causes of inherited deafness-blindness syndromes in humans. A fundamental reason for the current lack of treatment options for patients with these diseases is a limited understanding of the molecular basis for myosin VII function in the ear and eye. The proposed research focuses on understanding how myosin VII functions as a molecular motor to better understand how loss of myosin VII motor activity leads to deafness.