Structural and Dynamic Insights Into α-Synuclein Dimer Conformations

Abstract:

Parkinson's disease is associated with the aggregation of the protein α-synuclein. While α-synuclein can exist in multiple oligomeric states, the dimer has been a subject of extensive debates. Here, using an array of biophysical approaches, we demonstrate α-synuclein in vitro exhibits primarily a monomer-dimer equilibrium in nanomolar concentrations and up to a few micromolars. We then use spatial information from hetero-isotopic cross-linking mass spectrometry experiments as restrains in discrete molecular dynamics simulations to obtain the ensemble structure of dimeric species. Out of eight structural sub-populations of dimers we identify one that is compact, stable, abundant, and exhibits partially exposed β-sheet structures. This compact dimer is the only one where the hydroxyls of tyrosine 39 are in a proximity that can promote dityrosine covalent linkage implicated in amyloidogenesis. We propose that this α-synuclein dimer features etiological relevance to Parkinson's disease.

Publisher's Version

Last updated on 01/02/2022