Membrane trafficking at atomic resolution

Peripheral membrane proteins are essential for cellular trafficking and membrane remodelling, and have emerged as key determinants in many human disorders, including Alzheimer’s and Parkinson’s diseases, cancer, epilepsy and muscular dystrophy. This provides new opportunities for treating these conditions, but requires a much more detailed molecular understanding before such goals can be realised. Using cutting-edge structural, molecular and cellular approaches our lab aims to determine how these proteins control essential processes of cellular homeostasis, hormonal signaling, tissue morphogenesis, and neurosecretion in health and disease. 

1. The Retromer complex in endosomal sorting and neurodegeneration

   The Retromer complex is a peripheral membrane protein assembly that is essential for endosomal trafficking and is mutated in neurodegenerative diseases including Alzheimer’s and Parkinson’s. Our lab has made important contributions to the molecular understanding of retromer function and continues to use the techniques of X-ray crystallography and Electron Microscopy to study the principles that govern its assembly and dysfunction. 

2. Intracellular trafficking and membrane regulation by Sorting Nexins (SNXs)

   Sorting nexins are a large and diverse family of proteins with various roles in intracellular membrane transport and cell signalling. Their dysfunction is implicated in diseases including cancer, inflammation, genetic disorders and Alzheimer's disease, and they are emerging as therapeutic targets in these disorders. We aim to discover their mechanisms of action and to determine their potential for therapeutic development. 

3. The Commander protein complex in endosomal homeostasis

   Distantly related to the Retromer protein machinery, Commander is a recently identified endosome-associated protein complex. It plays important roles in endosomal sorting of cargos including integrins and lipoprotein receptors and rare mutations in Commander proteins lead to X-linked intellectual disability. We aim to capture a complete snapshot of how the many Commander subunits are integrated into a functional complex.

4. Caveola biogenesis and the role of the cavin proteins

   Caveolae are ~50 nm bud-like structures on the plasma membrane, with multiple roles in signal transduction, endocytosis and as sensors of membrane stress. In collaboration with Prof. Rob Partin (IMB, UQ) we aim to determine the molecular principles that govern the assembly of these critical protein-coated membrane vesicles. 

5. Regulation of neurosecretion by SNAREs and Munc18

   SNARE-mediated membrane fusion is required for regulated exocytosis and is critical in many cellular processes including neurosecretion, insulin secretion, immune responses and inflammation. The assembly of all SNARE complexes during membrane fusion is very tightly regulated by proteins of the Sec/Munc (SM) protein family that bind primarily to the syntaxin SNARE subunits and together with Prof. Fred Meunier (QBI, UQ) we are attempting to define the pathways and molecular interactions of SNARE and SM proteins that regulate neuronal synaptic function.