Musser, Siegfried Professor

The primary focus of my laboratory is to decipher how proteins partition into different sub-compartments of the cell. Cellular membranes serve to compartmentalize biochemical reactions to specific microenvironments. Proteins cross these membranes via a diverse array of protein translocation systems, or translocons. My laboratory has investigated the detailed molecular function of three different protein transport machineries, the human nuclear pore complex (NPC) and the bacterial Sec and Tat general secretion machineries. We are a biophysics lab and our primary tools for deciphering molecular mechanisms and dynamics are super-resolution imaging and single molecule particle tracking approaches. Our aim is to develop detailed, molecular-scale, mechanistic models of protein transport processes. We recently demonstrated 3D imaging of cargo transport through nuclear pores on the millisecond timescale with 5-15 nm precision in all three dimensions. This will be a major tool going forward for multiple projects.

In 2018, we began a new project on membrane-less organelles, which are micrometer-scale cellular structures known as biomolecular condensates (BMCs) that contain high concentrations of intrinsically disordered proteins and RNA. These BMCs are generally agreed to arise from liquid-liquid phase separation (LLPS), which is the spontaneous partitioning into dense and dilute phases due to favorable interactions between the separating molecules. The high density of aggregation prone proteins in BMCs is thought to lead to the cellular inclusions found in patients with multiple neurological diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Parkinson's and Alzheimer's diseases. We are using super-resolution and single molecule methods to probe the structural and dynamic heterogeneity of condensates formed from the fused in sarcoma (FUS) protein to identify the conditions that lead to solidification of liquid condensates (phase maturation).