%0 Journal Article
%A Shaykhalishahi, Hamed
%A Gauhar, Aziz
%A Wördehoff, Michael M.
%A Grüning, Clara S. R.
%A Klein, Antonia N.
%A Bannach, Oliver
%A Stoldt, Matthias
%A Willbold, Dieter
%A Härd, Torleif
%A Hoyer, Wolfgang
%T Contact between the β1 and β2 Segments of α-Synuclein that Inhibits Amyloid Formation
%J Angewandte Chemie / International edition
%V 54
%N 30
%@ 1433-7851
%C Weinheim
%I Wiley-VCH
%M FZJ-2015-07306
%P 8837 - 8840
%D 2015
%X Conversion of the intrinsically disordered protein α-synuclein (α-syn) into amyloid aggregates is a key process in Parkinson’s disease. The sequence region 35–59 contains β-strand segments β1 and β2 of α-syn amyloid fibril models and most disease-related mutations. β1 and β2 frequently engage in transient interactions in monomeric α-syn. The consequences of β1–β2 contacts are evaluated by disulfide engineering, biophysical techniques, and cell viability assays. The double-cysteine mutant α-synCC, with a disulfide linking β1 and β2, is aggregation-incompetent and inhibits aggregation and toxicity of wild-type α-syn. We show that α-syn delays the aggregation of amyloid-β peptide and islet amyloid polypeptide involved in Alzheimer’s disease and type 2 diabetes, an effect enhanced in the α-synCC mutant. Tertiary interactions in the β1–β2 region of α-syn interfere with the nucleation of amyloid formation, suggesting promotion of such interactions as a potential therapeutic approach.
%F PUB:(DE-HGF)16
%9 Journal Article
%U <Go to ISI:>//WOS:000358051600050
%$ pmid:26119103
%R 10.1002/anie.201503018
%U https://juser.fz-juelich.de/record/279291