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SUMMARY:Evolutionary strategies to prevent protein aggregation - Dr. Annal
 isa Pastore (National Institute for Medical Research\, London)
DTSTART:20100512T093000Z
DTEND:20100512T103000Z
UID:TALK24533@talks.cam.ac.uk
CONTACT:8272
DESCRIPTION:Protein aggregation is under intense scrutiny because of its r
 ole in human disease. Although increasing evidence indicates that protein 
 native states are highly protected against aggregation\, the specific prot
 ection mechanisms are poorly understood. Insight into such mechanisms can 
 be gained through study of the relatively few proteins that aggregate unde
 r native conditions. Ataxin-3\, the protein responsible for Spinocerebella
 r ataxia type 3\, a polyglutamine expansion disease\, represents one of su
 ch examples which we have used in our studies as a model system. Polygluta
 mine expansion is central for determining solubility and aggregation rates
  of ataxin-3\, but these properties are profoundly modulated by its N-term
 inal Josephin domain. We identified the regions that promote Josephin fibr
 illogenesis and rationalized the mechanisms that protect Josephin and non-
 expanded ataxin-3 from aberrant aggregation. Using different biophysical t
 echniques\, aggregation propensity predictions and rational design of amin
 oacid substitutions\, we show that Josephin has an intrinsic tendency to f
 ibrillize under native conditions and that fibrillization is promoted by t
 wo solvent-exposed patches\, which are also involved in recognition of nat
 ural substrates\, such as ubiquitin. Designed mutations at these patches o
 r substrate binding significantly reduce Josephin aggregation kinetics. Ou
 r results provide evidence that protein non-pathologic function can play a
 n active role in preventing aberrant fibrillization and suggest a general 
 model to understand aggregation.
LOCATION:Unilever Lecture Theatre\, Unilever Centre\, Department of Chemis
 try
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