Effect of acidic pH on the stability of α-synuclein dimers. Academic Article uri icon

Overview

MeSH

  • Amino Acid Substitution
  • Humans
  • Hydrogen-Ion Concentration
  • Mutation, Missense
  • Protein Structure, Quaternary
  • Static Electricity

MeSH Major

  • Protein Aggregates
  • Protein Multimerization
  • alpha-Synuclein

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. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 715-724, 2016. © 2016 Wiley Periodicals, Inc.

publication date

  • October 2016

has subject area

  • Amino Acid Substitution
  • Humans
  • Hydrogen-Ion Concentration
  • Mutation, Missense
  • Protein Aggregates
  • Protein Multimerization
  • Protein Structure, Quaternary
  • Static Electricity
  • alpha-Synuclein

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4958566

Digital Object Identifier (DOI)

  • 10.1002/bip.22874

PubMed ID

  • 27177831

Additional Document Info

start page

  • 715

end page

  • 724

volume

  • 105

number

  • 10