Biochemistry of membrane dynamics
Ferlins are a multi C2 domain protein family critical for vesicle fusion and membrane trafficking. Members of the ferlin family are linked to detrimental pathogenic conditions such as deafness (otoferlin) and muscular dystrophy (dysferlin and myoferlin) in human patients. A characteristic feature of ferlins is their remarkable number of C2 domains (5 to 7) which are anchored in lipid membranes through their C-terminal transmembrane domain. The capability of their C2 domains to bind calcium ions and phospholipids led to the initial view that ferlins act as calcium sensors for membrane fusion events, similar to the well-studied family of synaptotagmins. However, recent findings suggest that ferlin family members engage in roles beyond that, which to date, we do not fully understand.
One of the ferlin family members we are particularly interested in is otoferlin. It plays a key role in neurotransmission of auditory synapses, which substantially differs from the classical neuronal neurotransmission. Studies suggest that otoferlin might operate at the level of vesicle priming and fusion, however, the molecular mechanism by which it regulates neurotransmission is largely unresolved. Specifically, we do not understand how exactly otoferlin promotes priming and fusion, and to which extent these processes depend on calcium and phospholipids, or additional interaction partners.
In addition to otoferlin, we focus our studies on dysferlin. It is crucial for the membrane repair process in muscle cells, potentially as a calcium sensor that triggers membrane fusion. Beyond that, several interactions of dysferlin with other proteins are suggested to promote membrane resealing. However, the precise dysferlin-dependent repair mechanism remains unclear.
In our group, we aim to understand the roles of ferlins with a focus on otoferlin and dysferlin and how they are altered in human disease. To this end, we study these proteins outside of their complex cellular environment and reconstitute purified ferlins in artificial membranes. This strategy allows us to directly control individual components, identify how ferlin function relies on the presence of calcium, phospholipids or interacting partners and ultimately arrive at a fundamental understanding of the underlying mechanisms. We combine this bottom up approach with biochemical and biophysical methodologies and structural biology techniques including single particle cryo electron microscopy and X-ray crystallography.