Structural mechanics in subcellular structure formation (360G-Wellcome-211193_Z_18_Z)

A failure to properly build and maintain cellular structures leads to cell- death or disease. Yet, the regulation and mechanisms of the machinery that coordinate such structures are generally poorly understood. The formation and maintenance of many cellular substructures is dependent on the receipt and retention of specific components, selected through tethering complexes. Of particular interest is the exocyst complex, whose role in polarized trafficking leads in part to the spatially and physically distinct cilia and tight junction membrane substructures. I hypothesize that membranes and combinations of their signaling proteins coordinate the mechanics of the polarized trafficking machinery through the exocyst. I will determine how this complex assembles and targets specific membranes through an innovative reconstitution combining biophysical and cell biological approaches. Through synergy with structural methods, the outcome of this approach will be information on the relationship between structure and functional mechanism on membranes, and the cellular consequence of exocyst spatiotemporal regulation. The imbalances of polarized trafficking in both aberrant development and cancers urge a program aimed at resolving the molecular mechanics of this pathway.