Self-organizing macromolecular collectives in the cytoplasm
Our understanding of complex molecular machines, such as the ribosome, has increased significantly in recent years but we still know surprisingly little about the ways in which macromolecules are spatiotemporally organized in the cytoplasm of living cells. Recent data indicate that the cytoplasm is not uniform but structured into functionally distinct, phase-separated compartments. Well known examples of such compartments are RNA-containing cytoplasmic bodies, which form in an orchestrated response to diverse external and internal stimuli. The molecular mechanisms that govern their assembly, 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 assemble into compartments are diverse, involving factor-assisted and factor-independent ways of association. The ability to transition into a different phase seems to come at a cost, however, because many phase-separating proteins have a 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 sequence patterns, domains and proteins that promote the assembly of macromolecular complexes and/or the formation of protein aggregates
Analyze the molecular mechanisms behind protein aggregation/protein body formation with a focus on the protein quality control machinery, protein kinases and the cytoskeleton
Investigate how the ability to form macromolecular assemblies affects the physiological state of a cell, determines developmental decisions, and contributes to aging
Perform proteome-wide screens to identify genetic modifiers of protein body formation and/or protein aggregation
Malinovska, Liliana; Kroschwald, Sonja; Alberti, Simon
Protein disorder, prion propensities, and self-organizing macromolecular collectives.