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Angew Chem Int Ed Engl. 2015 Jul 20;54(30):8837-40. doi: 10.1002/anie.201503018. Epub 2015 Jun 26.

Contact between the β1 and β2 Segments of α-Synuclein that Inhibits Amyloid Formation.

Author information

1
Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40204 Düsseldorf (Germany).
2
Strukturbiochemie (ICS-6), Forschungszentrum Jülich, 52425 Jülich (Germany).
3
Department of Chemistry and Biotechnology, Swedish University of Agricultural Sciences (SLU), 750 07 Uppsala (Sweden).
4
Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40204 Düsseldorf (Germany). Wolfgang.Hoyer@uni-duesseldorf.de.
5
Strukturbiochemie (ICS-6), Forschungszentrum Jülich, 52425 Jülich (Germany). Wolfgang.Hoyer@uni-duesseldorf.de.

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.

KEYWORDS:

aggregation; intrinsically disordered proteins; protein engineering; protein folding; protein-protein interactions

PMID:
26119103
DOI:
10.1002/anie.201503018
[Indexed for MEDLINE]

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