The condensation of proteins with low complexity sequences plays both functional and pathogenic roles in living cells. Recent efforts to understand the chemistry of biomolecular condensates have revealed that protein sequences harboring weak and dynamic multivalent interaction sites produce the macroscopic behavior observed in living cells. The hydrogen bonding, cation-π, π-π, dipole-dipole, and cation-anion interactions involved are well understood individually, yet fundamental and intriguing questions remain regarding how this chemistry works in specific biological contexts at the structural level. Our current efforts focus on two condensation mechanisms involving β-strand mediated hydrogen bond interactions. First, we aim to understand how dynamic and functional liquid droplets formed by the low complexity domains of RNA-binding proteins transition into rigid fibrillar hydrogels, a chemical process that underlies disease pathology. Our recent work provides evidence for competing β-strand interactions in the TAR DNA-binding protein 43 (TDP-43) low complexity domain and shows that the region thought to be most important for pathological aggregation is not the most stable in the mature liquid droplets. Second, we aim to understand how functional liquid droplets are spatially localized in living cells though heterogeneous intermolecular interactions between low complexity protein domains. To this end, we are characterizing the low complexity domains present in the cell cytoskeleton. Our first step in this direction reveals that a dynamic assembly of β-strands in the low complexity domain of an intermediate filament protein is essential for the formation of the mature biological assembly. Through these two avenues of research, we are forging an understanding of how low complexity protein domains facilitate complex chemical interactions in living cells to achieve specific biological functions and how these interactions are altered in neurodegenerative disease.

β-strand mediated biological condensation mechanisms

ACS Fall 2021

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