Structural and dynamic insights into α-synuclein dimer conformations

• Published in: Structure (London) 2023-04, Vol.31 (4), p.411-423.e6
• Main Authors: Zamel, Joanna, Chen, Jiaxing, Zaer, Sofia, Harris, Paul David, Drori, Paz, Lebendiker, Mario, Kalisman, Nir, Dokholyan, Nikolay V., Lerner, Eitan
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - chemistry; Amyloid - chemistry; cross-linking mass spectrometry; dimer; discrete molecular dynamics; Humans; Molecular Conformation; Parkinson Disease - etiology; Parkinson Disease - metabolism; synuclein
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2023.01.011

Parkinson 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 that 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 proximity that may promote dityrosine covalent linkage upon hydroxyl radicalization, which is implicated in α-synuclein amyloid fibrils. We propose that this α-synuclein dimer features etiological relevance to Parkinson disease. [Display omitted] •α-Synuclein exists mostly as monomers or dimers at few micromolars at most•Experimentally driven computational prediction of α-synuclein dimer structures•The stable and frequent conformation of the α-synuclein dimer is compact•An α-synuclein dimer conformation exhibits proximity between tyrosine 39 residues Self-association of the protein α-synuclein into amyloid-like fibers is a well-known hallmark of Parkinson disease. Initial stages of amyloid-like fiber formation involve oligomerization, and the most basic oligomer is a dimer. Using experiments and computations, Zamel, Chen et al. report the structures of conformations of the α-synuclein dimer.