Modification of α-synuclein for inhibition of nucleation and elongation of amyloid fibrils

Add to your list(s) Download to your calendar using vCal

• Prof Wolfgang Hoyer, Junior Professor of Chemical Biology of Protein Aggregation, Institute for Physical Biology, Heinrich-Heine-University Düsseldorf
• Wednesday 08 February 2023, 10:30-11:30
• Department of Chemistry, Unilever Lecture Theatre.

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

Aggregation of the intrinsically disordered protein α-synuclein (αSyn) into amyloid fibrils is involved in Parkinson’s disease and other synucleinopathies. The region comprising residues 36-56 is an interaction hotspot and regulates aggregation. Here, we report how modification of this critical region affects the individual reaction steps of fibril formation. We pursued two modification strategies: A) binding of the critical region by the engineered binding protein β-wrapin AS69 ; B) sequence changes leading to, e.g., intramolecular disulfide bonds within the critical 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 efficiency is determined by the specific modification of the critical region, but also depends on the presence of intrinsically disordered regions of αSyn adjacent to the interaction hotspot. Fusion of wild-type αSyn to the inhibitor molecules enhances the inhibitory potential. Our results provide insight into interactions at fibril ends and lateral surfaces, into fibril elongation and secondary nucleation. The work demonstrates how modification of the conformational properties of αSyn can result in efficient inhibition of specific steps of the amyloid formation reaction.

This talk is part of the Biophysical Seminars series.

This talk is included in these lists:

• All Talks (aka the CURE list)
• Biophysical Seminar Series 2016/17
• Biophysical Seminars
• Department of Chemistry
• Department of Chemistry, Unilever Lecture Theatre
• Featured lists
• School of Physical Sciences

Note that ex-directory lists are not shown.