title: Contact between the β1 and β2 Segments of α-Synuclein that Inhibits Amyloid Formation.
abstract: 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.
authors.affiliation: Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40204 Düsseldorf (Germany).
authors.forename: Hamed
authors.initials: H
authors.lastname: Shaykhalishahi
authors.affiliation: Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40204 Düsseldorf (Germany).
authors.forename: Aziz
authors.initials: A
authors.lastname: Gauhar
authors.affiliation: Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40204 Düsseldorf (Germany).
authors.forename: Michael M
authors.initials: MM
authors.lastname: Wördehoff
authors.affiliation: Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40204 Düsseldorf (Germany).
authors.forename: Clara S R
authors.initials: CS
authors.lastname: Grüning
authors.affiliation: Strukturbiochemie (ICS-6), Forschungszentrum Jülich, 52425 Jülich (Germany).
authors.forename: Antonia N
authors.initials: AN
authors.lastname: Klein
authors.affiliation: Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40204 Düsseldorf (Germany).|Strukturbiochemie (ICS-6), Forschungszentrum Jülich, 52425 Jülich (Germany).
authors.forename: Oliver
authors.initials: O
authors.lastname: Bannach
authors.affiliation: Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40204 Düsseldorf (Germany).|Strukturbiochemie (ICS-6), Forschungszentrum Jülich, 52425 Jülich (Germany).
authors.forename: Matthias
authors.initials: M
authors.lastname: Stoldt
authors.affiliation: Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40204 Düsseldorf (Germany).|Strukturbiochemie (ICS-6), Forschungszentrum Jülich, 52425 Jülich (Germany).
authors.forename: Dieter
authors.initials: D
authors.lastname: Willbold
authors.affiliation: Department of Chemistry and Biotechnology, Swedish University of Agricultural Sciences (SLU), 750 07 Uppsala (Sweden).
authors.forename: Torleif
authors.initials: T
authors.lastname: Härd
authors.affiliation: Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40204 Düsseldorf (Germany). Wolfgang.Hoyer@uni-duesseldorf.de.|Strukturbiochemie (ICS-6), Forschungszentrum Jülich, 52425 Jülich (Germany). Wolfgang.Hoyer@uni-duesseldorf.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hoyer
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008958:Models, Molecular; D066329:Protein Aggregates; D017510:Protein Folding; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D000682:Amyloid; D066329:Protein Aggregates; D051844:alpha-Synuclein
keywords: aggregation; intrinsically disordered proteins; protein engineering; protein folding; protein-protein interactions