Structural elucidation of the self-assembly mechanism of amyloid fibrils

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• Sheena Radford, University of Leeds
• Wednesday 25 February 2009, 11:00-12:00
• Unilever Lecture Theatre, Unilever Centre, Department of Chemistry.

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Understanding how different proteins assemble into the ordered, insoluble aggregates associated with amyloid disease is a formidable challenge. Whilst it is generally accepted that protein unfolding is required for the formation of amyloid fibrils from natively folded proteins in vitro and, therefore, presumably also in vivo, the point at which the folding and aggregation free energy landscapes diverge, and the role of different amino acid residues in determining folding versus aggregation, remain obscure. We have attempted to address this question by determining the mechanisms of protein folding and aggregation of the naturally amyloidogenic protein, beta-2-microglobulin, under different solution conditions Using NMR the conformational properties of species that initiate the amyloid cascade have been identified and an array of mutants have been created to explore the role of individual residues in governing the rates of aggregation. Even more challenging, however, is the identification of early oligomeric species and their structural characterisation, since such species are aggregation-prone, short-lived and rapidly equilibrating. Using an array of different biophysical methods and approaches, our aim is to elucidate the mechanism of amyloid formation of this protein in atomistic detail, so as to provide new fundamental understandings of protein-protein recognition in amyloid assembly that may help to pave the way towards therapeutic intervention.

This talk is part of the Biophysics Colloquia - (Chemistry) series.

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