Pathogenic vs. Reversible Amyloid & Inhibition of Aggregation

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• Prof David Eisenberg, Howard Hughes Medical Institute, UCLA-DOE Institute, Departments of Biological Chemistry and Chemistry & Biochemistry, UCLA, Los Angeles, California, USA
• Wednesday 01 March 2017, 11:00-12:00
• Department of Chemistry, Cambridge, Pfizer lecture theatre.

If you have a question about this talk, please contact Priyanka Joshi.

Control of metabolism by compartments is a characteristic of higher cells. Recent studies have focused on such dynamic intracellular bodies, inclusions such as stress granules, P-bodies, nucleoli, and metabolic puncta. These bodies appear as separate phases, some containing reversible, amyloid-like fibrils formed by interactions of low-complexity protein domains. We have determined four atomic structures of segments of low-complexity domains from inclusion-forming proteins, one determined to 1.1 Å resolution by micro-electron diffraction. These interacting protein segments show common characteristics, all in contrast to pathogenic amyloid: kinked peptide backbones, smaller surface areas of interaction, and domination by interacting aromatic side-chains. By threading the human proteome on our four kinked structures, we identified more than 1000 low complexity domains potentially capable of forming such reversible interactions. These segments lie in proteins as diverse as RNA binders, nuclear pore proteins, keratins, and cornified envelope proteins, consistent with the capacity of cells to form a wide variety of dynamic intracellular bodies. In recent work on pathogenic amyloid, we have designed inhibitors of aggregation based on atomic structures of segments that drive aggregation.

This talk is part of the Biophysical Seminars series.

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