We report our recent progress characterizing the assembly of cross-β fibrils formed by the low complexity sequence domains of two RNA-binding proteins and one intermediate filament protein. In living cells, domains with a reduced diversity of amino acid types mediate protein-protein interactions that are involved in various aspects of RNA metabolism and have an unknown function in the intermediate filament networks of the cell cytoskeleton. If left unregulated, these protein domains facilitate the formation of pathological aggregates in the neurons of patients with neurodegenerative disease. These assembly processes are broadly classified as forms of biomolecular condensation, a phenomenon driven by a continuum of molecular conformations, ranging from dynamic and disordered to rigid and ordered. Liquid-liquid phase separations and cross-β fibril structures represent two extremes of this continuum. It is surprising that protein sequences enriched in only a few amino acid types can associate through transient interactions in certain circumstances and adopt highly specific conformations in others. Our solid state nuclear magnetic resonance measurements combined with kinetic and thermodynamic assays provide high-resolution and sequence-specific information regarding the molecular interactions responsible for the assembly processes of these proteins. The results will further our understanding of the fundamental protein physical chemistry underlying biomolecular condensation and will improve the detection and treatment of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.<br/>

Molecular mechanisms for low complexity sequence protein assembly

ACS Fall 2020 Virtual Meeting

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