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

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. A stable intramolecular contact between the β1 and β2 sequence segments of the intrinsically disordered protein α‐synuclein is established by disulfide engineering. The resulting protein does not form oligomers or amyloid fibrils, and inhibits aggregation and toxicity of the amyloidogenic proteins α‐synuclein, amyloid‐β, and islet amyloid polypeptide. Tertiary interactions in the β1–β2 region of α‐synuclein interfere with amyloid formation.