Contact between the [beta]1 and [beta]2 Segments of [alpha]-Synuclein that Inhibits Amyloid Formation

Conversion of the intrinsically disordered protein [alpha]-synuclein ([alpha]-syn) into amyloid aggregates is a key process in Parkinson's disease. The sequence region 35-59 contains [beta]-strand segments [beta]1 and [beta]2 of [alpha]-syn amyloid fibril models and most disease-related mutations. [beta]1 and [beta]2 frequently engage in transient interactions in monomeric [alpha]-syn. The consequences of [beta]1-[beta]2 contacts are evaluated by disulfide engineering, biophysical techniques, and cell viability assays. The double-cysteine mutant [alpha]-synCC, with a disulfide linking [beta]1 and [beta]2, is aggregation-incompetent and inhibits aggregation and toxicity of wild-type [alpha]-syn. We show that [alpha]-syn delays the aggregation of amyloid-[beta] peptide and islet amyloid polypeptide involved in Alzheimer's disease and type2 diabetes, an effect enhanced in the [alpha]-synCC mutant. Tertiary interactions in the [beta]1-[beta]2 region of [alpha]-syn interfere with the nucleation of amyloid formation, suggesting promotion of such interactions as a potential therapeutic approach.