Sammanfattning

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.

Nyckelord

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

Publicerad i

Angewandte Chemie International Edition
2015, Volym: 54, nummer: 30, sidor: 8837-8840
Utgivare: WILEY-V C H VERLAG GMBH

SLU författare

• Härd, Torleif

  • Institutionen för kemi och bioteknologi, Sveriges lantbruksuniversitet
    

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UKÄ forskningsämne

Cellbiologi
Neurovetenskaper


Publikationens identifierare

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

Permanent länk till denna sida (URI)

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