Structure and function in desmosomal junctions. (360G-Wellcome-094303_Z_10_Z)

Our overall goal is to elucidate the structural mechanisms of the desmosomal proteins in sufficient molecular detail to understand their specific roles in skin and heart disease and wound healing at a level which informs rational diagnostic and therapeutic design. The project will build on our previously published work on the structural biology of the desmoglein cytoplasmic domain and will address three novel areas of desmosome biology. First, it will highlight the role of intrinsically disord ered regions and inducible structures in the interactions of proteins and conserved elements within the desmosome using circular dichroism and nuclear magnetic resonance (NMR) spectroscopy. Second, it will show that desmosomal proteins exhibit differential interactions with each other by mapping the binding specificities and stochiometries of complexes within tissue-specific systems by surface plasmon resonance detection and analytical ultracentrifugation experiments. Finally, we will solve th e solution structure of the plakin domain of desmoplakin, and show for the first time the effects of human ARVC mutations at the molecular level using NMR and small angle X-ray scattering alongside quantitative binding studies. Together this will provide a more comprehensive, structural biological view of the cytoskeletal machinery that dictates cell adhesion and signaling within the desmosome.