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Contact between the β1 and β2 Segments of α‐Synuclein that Inhibits Amyloid Formation
Author(s) -
Shaykhalishahi Hamed,
Gauhar Aziz,
Wördehoff Michael M.,
Grüning Clara S. R.,
Klein Antonia N.,
Bannach Oliver,
Stoldt Matthias,
Willbold Dieter,
Härd Torleif,
Hoyer Wolfgang
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201503018
Subject(s) - amyloid (mycology) , mutant , chemistry , fibril , cysteine , protein aggregation , biophysics , peptide , protein folding , wild type , alpha synuclein , biochemistry , microbiology and biotechnology , biology , disease , medicine , parkinson's disease , gene , enzyme , inorganic chemistry
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.