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SUMMARY:Modification of α-synuclein for inhibition of nucleation and elon
 gation of amyloid fibrils - Prof Wolfgang Hoyer\, Junior Professor of Chem
 ical Biology of Protein Aggregation\, Institute for Physical Biology\, Hei
 nrich-Heine-University Düsseldorf
DTSTART:20230208T103000Z
DTEND:20230208T113000Z
UID:TALK196966@talks.cam.ac.uk
CONTACT:Alyssa Miller
DESCRIPTION:Aggregation of the intrinsically disordered protein α-synucle
 in (αSyn) into amyloid fibrils is involved in Parkinson’s disease and o
 ther synucleinopathies. The region comprising residues 36-56 is an interac
 tion hotspot and regulates aggregation. Here\, we report how modification 
 of this critical region affects the individual reaction steps of fibril fo
 rmation. We pursued two modification strategies: A) binding of the critica
 l region by the engineered binding protein β-wrapin AS69\; B) sequence ch
 anges leading to\, e.g.\, intramolecular disulfide bonds within the critic
 al region. We performed extensive protein engineering\, chemical kinetics\
 , and AFM to elucidate how interference with the critical region leads to 
 strongly substoichiometric inhibition of secondary nucleation (strategy A)
  or fibril elongation (strategy B). For both strategies\, the inhibitory e
 fficiency is determined by the specific modification of the critical regio
 n\, but also depends on the presence of intrinsically disordered regions o
 f αSyn adjacent to the interaction hotspot. Fusion of wild-type αSyn to 
 the inhibitor molecules enhances the inhibitory potential. Our results pro
 vide insight into interactions at fibril ends and lateral surfaces\, into 
 fibril elongation and secondary nucleation. The work demonstrates how modi
 fication of the conformational properties of αSyn can result in efficient
  inhibition of specific steps of the amyloid formation reaction.\n 
LOCATION:Department of Chemistry\, Unilever Lecture Theatre
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