Effect of acidic pH on the stability of α-synuclein dimers

Zhengjian Lv, Alexey V. Krasnoslobodtsev, Yuliang Zhang, Daniel Ysselstein, Jean Christophe Rochet, Scott C. Blanchard, Yuri L. Lyubchenko

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Environmental factors, such as acidic pH, facilitate the assembly of α-synuclein (α-Syn) in aggregates, but the impact of pH on the very first step of α-Syn aggregation remains elusive. Recently, we developed a single-molecule approach that enabled us to measure directly the stability of α-Syn dimers. Unlabeled α-Syn monomers were immobilized on a substrate, and fluorophore-labeled monomers were added to the solution to allow them to form dimers with immobilized α-Syn monomers. The dimer lifetimes were measured directly from the fluorescence bursts on the time trajectories. Herein, we applied the single-molecule tethered approach for probing of intermolecular interaction to characterize the effect of acidic pH on the lifetimes of α-Syn dimers. The experiments were performed at pH 5 and 7 for wild-type α−Syn and for two mutants containing familial type mutations E46K and A53T. We demonstrate that a decrease of pH resulted in more than threefold increase in the α-Syn dimers lifetimes with some variability between the α-Syn species. We hypothesize that the stabilization effect is explained by neutralization of residues 96–140 of α-Syn and this electrostatic effect facilitates the association of the two monomers. Given that dimerization is the first step of α-Syn aggregation, we posit that the electrostatic effect thereby contributes to accelerating α-Syn aggregation at acidic pH.

Original languageEnglish (US)
Pages (from-to)715-724
Number of pages10
JournalBiopolymers
DOIs
StatePublished - Oct 1 2016

Keywords

  • alpha-synuclein protein
  • amyloid aggregation
  • interprotein interactions
  • protein self-assembly
  • single molecule fluorescence

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Biomaterials
  • Organic Chemistry

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