Structural and dynamic insights into ?-synuclein dimer conformations

摘要

Parkinson disease is associated with the aggregation of the protein a-synuclein. While a-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 that a-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 dy-namics simulations to obtain the ensemble structure of dimeric species. Out of eight structural sub -popula-tions of dimers, we identify one that is compact, stable, abundant, and exhibits partially exposed b-sheet structures. This compact dimer is the only one where the hydroxyls of tyrosine 39 are in proximity that may promote dityrosine covalent linkage upon hydroxyl radicalization, which is implicated in a-synuclein am-yloid fibrils. We propose that this a-synuclein dimer features etiological relevance to Parkinson disease.