Regulation of amyloid self-assembly under partially denaturing solution conditions

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• Prof Martin Muschol (University of South Florida)
• Thursday 10 June 2010, 16:00-17:00
• Unilever Lecture Theatre, Department of Chemistry.

If you have a question about this talk, please contact Dr Mark Miller.

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Accumulation of insoluble protein fibrils is a hallmark of multiple organ-specific and systemic human disorders, including Alzheimer’s disease, Parkinson’s disease and type-II diabetes. Understanding the molecular and cellular mechanisms regulating and promoting the formation of such amyloid fibrils in vitro and in vivo represents a major challenge both for basic scientists and health care professionals.

Our laboratory is interested in identifying overarching physical principles regulating the self-assembly of amyloidogenic proteins into mature fibrils. We’ve been studying amyloid formation using the native folded protein hen egg-white lysozyme. Combining in-situ dynamic light scattering (DLS) with atomic force microscopy (AFM), fluorescence and CD-spectroscopy we have investigated how in-vitro growth conditions affect the nucleation and growth kinetics as well as the assembly pathways of amyloid fibril formation under partially denaturing conditions. We found that lysozyme displayed three different growth regimes characterized by distinct nucleation and growth kinetics, diverse intermediate aggregate species and changes in net protein interactions. At low salt concentrations amyloid self-assembly proceeds via polymerization of monomeric species. As salt concentration increases compact oligomer form which subsequently assemble into larger polymers. Eventually, ordered fibril assembly transitions into disordered precipitation. Our data further suggest that amyloid fibril assembly proceeds under conditions of net protein repulsion which is the opposite to conditions favorable for protein crystallization. We will discuss the evidence for the conclusions and suggest a simple model to explain both the observed transitions in fibril assembly pathways and the differences in solution conditions promoting fibril formation vs. crystallization.

This talk is part of the Extra Theoretical Chemistry Seminars series.

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