University of Cambridge > > Biophysics Colloquia - (Chemistry) > Evolutionary strategies to prevent protein aggregation

Evolutionary strategies to prevent protein aggregation

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Protein aggregation is under intense scrutiny because of its role in human disease. Although increasing evidence indicates that protein native states are highly protected against aggregation, the specific protection mechanisms are poorly understood. Insight into such mechanisms can be gained through study of the relatively few proteins that aggregate under native conditions. Ataxin-3, the protein responsible for Spinocerebellar ataxia type 3, a polyglutamine expansion disease, represents one of such examples which we have used in our studies as a model system. Polyglutamine expansion is central for determining solubility and aggregation rates of ataxin-3, but these properties are profoundly modulated by its N-terminal Josephin domain. We identified the regions that promote Josephin fibrillogenesis and rationalized the mechanisms that protect Josephin and non-expanded ataxin-3 from aberrant aggregation. Using different biophysical techniques, aggregation propensity predictions and rational design of aminoacid substitutions, we show that Josephin has an intrinsic tendency to fibrillize under native conditions and that fibrillization is promoted by two solvent-exposed patches, which are also involved in recognition of natural substrates, such as ubiquitin. Designed mutations at these patches or substrate binding significantly reduce Josephin aggregation kinetics. Our results provide evidence that protein non-pathologic function can play an active role in preventing aberrant fibrillization and suggest a general model to understand aggregation.

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

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