COBRE for the Center for Molecular Medicine: Scope - Relationship of the Project to the Molecular Basis of Human Disease

The GIPC family of proteins function as key molecular scaffolds that are critical in the physical integration of multiple steps of signaling from receptor activation to intracellular signaling. GIPC3 plays an essential role in the auditory system, with mutations in GIPC3 causing inherited nonsyndromic hearing loss. Despite this unique and crucial function in the auditory system, the molecular function and why mutations in the GIPC3 gene leads to hearing loss, is unknown. We will define the structural basis for GIPC3 function, and the mechanism(s) by which the eleven reported patient mutations lead to inherited hearing loss. Defining the structure and functional interactions of GIPC3, and the molecular basis for dysfunction, requires an integrated structural, biochemical, and physiological approach that form the heart of our proposed work. In Aim 1, we will determine the basis for GIPC3 coupling to the NMDA glutamate receptor. Aim 2 will focus on conformational dynamics associated with activation of GIPC3, and how this leads to engagement of the Myo6 motor protein. Taken together, these studies contribute to our long-term goal of understanding the physical mechanisms underlying the role GIPC3 in normal physiological function, and will inform ongoing efforts to understand and ameliorate GIPC3 dysfunction in disease.