Modulation of Intramolecular Diffusion in Intrinsically Disordered Protein α-Synuclein under Aggregating Conditions

Abstract

It is generally accepted that aggregation takes place from partially unstructured states of initially globular proteins or unstructured states of intrinsically disordered peptides or proteins. However, we know very little about the elementary steps of protein aggregation.The intramolecular diffusion due to formation of contact between two points in a polypeptide chain may be the earliest step of the folding and also aggregation. It is not yet known how intramolecular diffusion of a polypeptide chain is affected under aggregating conditions. In particular it is unknown whether the rate of intramolecular diffusion under physiological conditions is decreased/increased or completely vanished under aggregating conditions. We have addressed this issue by studying the intramolecular contacts formation in an intrinsically disordered protein, α-synuclein under both physiological and aggregating conditions. At low temperatures, the rate of intramolecular diffusion is quite high, comparable to unstructured model peptides. However this rate decreases with increasing temperature, suggesting that the protein reconfigures more slowly under aggregating conditions.