Multi-Pronged Interactions Underlie Inhibition of ?-Synuclein Aggregation by ?-Synuclein.

ABSTRACT: The intrinsically disordered protein ?-synuclein is known to inhibit the aggregation of its intrinsically disordered homolog, ?-synuclein, which is implicated in Parkinson's disease. While ?-synuclein itself does not form fibrils at the cytoplasmic pH?7.4, alteration of pH and other environmental perturbations are known to induce its fibrilization. However, the sequence and structural determinants of ?-synuclein inhibition and self-aggregation are not well understood. We have utilized a series of domain-swapped chimeras of ?-synuclein and ?-synuclein to probe the relative contributions of the N-terminal, C-terminal, and the central non-amyloid-? component domains to the inhibition of ?-synuclein aggregation. Changes in the rates of ?-synuclein fibril formation in the presence of the chimeras indicate that the non-amyloid-? component domain is the primary determinant of self-association leading to fibril formation, while the N- and C-terminal domains play critical roles in the fibril inhibition process. Our data provide evidence that all three domains of ?-synuclein together contribute to providing effective inhibition, and support a model of transient, multi-pronged interactions between IDP chains in both processes. Inclusion of such multi-site inhibitory interactions spread over the length of synuclein chains may be critical for the development of therapeutics that are designed to mimic the inhibitory effects of ?-synuclein.

SUBMITTER: Williams JK 

PROVIDER: S-EPMC6100766 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature