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

Published in

Angewandte Chemie International Edition
2015, Volume: 54, number: 30, pages: 8837-8840
Publisher: WILEY-V C H VERLAG GMBH

SLU Authors

• Härd, Torleif

  • The Department of Chemistry and Biotechnology, Swedish University of Agricultural Sciences
    

Sustainable Development Goals

Ensure healthy lives and promote well-being for all at all ages


UKÄ Subject classification

Cell Biology
Neurosciences


Publication identifier

DOI: https://doi.org/10.1002/anie.201503018

Permanent link to this page (URI)

https://res.slu.se/id/publ/73425