Macromolecular assemblies and the organization of cytoplasm across space and time
Our understanding of complex molecular machines has increased significantly in recent years, but we still have a very limited understanding of how macromolecules are spatiotemporally organized in the cell. The cytoplasm contains several membrane-enclosed organelles but also a multitude of macromolecular assemblies that are not surrounded by membranes. These non membrane-bound assemblies can adopt considerable sizes, thus occupying an intermediate length scale located between the nanoscale of individual macromolecules and the microscale of cells. Well known examples of such mesoscale assemblies are RNA-containing stress granules and processing bodies, which form in an orchestrated response to diverse external and internal stimuli. The molecular mechanisms that govern the formation of such complex macromolecular collectives, however, have so far remained elusive.
Our goal is to elucidate the molecular principles underlying the spatiotemporal organization of proteins and RNAs in the cytoplasm. To do this, we are using cell biological, biochemical, and genetic approaches and diverse model systems such as yeast, Dictyostelium, and cultured mammalian cells. Our findings so far indicate that the mechanisms by which macromolecules form higher order assemblies are diverse, involving mechanisms of self-assembly and factor-assisted ways of intermolecular association. However, the ability to assemble into higher order structures seems to come at a cost, because many proteins in phase-separating assemblies have an unusually high propensity to misfold and aggregate. Therefore, we are also interested in understanding how pathological protein conformations can result from aberrant interactions between phase-separating proteins. Consequently, we hope that these studies improve our understanding of protein misfolding disorders, such as Huntington’s, Alzheimer's or Parkinson's disease.
Identify proteins, domains, and sequence motifs that are required for the formation of macromolecular assemblies.
Analyze the molecular mechanisms underlying the formation of macromolecular assemblies, with a focus on the protein quality control machinery, protein kinases, and the cytoskeleton.
Proteome-wide screens to identify genetic modifiers of macromolecular assemblies.
Investigate how the ability to form macromolecular assemblies affects the physiological state of a cell, determines developmental decisions, and contributes to aging and disease.