NHMRC Career Development Fellowship (R.D. Wright Biomedical CDF Level 2): Peripheral membrane proteins in health and disease (2014-2017)

Using a combination of structural and molecular cell biology I aim to determine how peripheral membrane proteins control membrane remodeling and trafficking. Many disorders are caused by disruptions in these molecular machines, including Alzheimer and Parkinson diseases, cancer, and muscular dystrophy, due to their importance in essential processes including cellular homeostasis, signaling, tissue morphogenesis, and neurosecretion. The fellowship will be organised around four themes: 1. Intracellular trafficking and signal regulation by Sorting Nexins (SNXs). How do SNX proteins function, and can we target them for new therapies? 2. The retromer complex in endosomal sorting and neurodegeneration. How does retromer recognize cellular cargos? What impact do Parkinson disease-causing mutations have on retromer function? 3. Caveolae biogenesis and the role of the cavin proteins. How are caveolae generated by cavins and what effect do mutations in these proteins have? 4. Regulation of neurosecretion by SNAREs and Munc18. How does Munc18-1, mutated in infantile epilepsy, regulate neurosecretion? I will address these questions using a multi-disciplinary collaborative approach, integrating structure determination by X-ray crystallography and NMR with biochemical and cellular experiments guided by our mechanistic insights. Structures of the protein complexes will allow us to understand how they interact with each other, with membrane environments, and how mutations alter their function. We will be able to determine the effect of disease causing mutations, and design site-specific mutants to probe their interactions and functions in vitro and in vivo.