Integrative structure models of the α-Synuclein dimer conformations

α-Synuclein is an intrinsically disordered protein known for its contributions to functions in neurons but mostly in its contributions to the development of Parkinson's disease via formation of self-associated forms, fibrils and Lewy bodies. Among the multiple targets it interacts with and gains a folded structure within the bound state, are homo-oligomers. Logically, the shortest homo-oligomer a protein can form is a dimer. However, until today the existence of the α-Synuclein dimer has been a subject of much debate. Using an array of measurements, we show that in vitro α-Synuclein exhibits primarily a monomer-dimer equilibrium within a concentration range of hundreds of nanomolars and up to a few micromolars. Furthermore, we performed hetero-isotopic cross-linking mass spectrometry experiments, from which we gained spatial information on the dimer that was then used in constructing restraints for discrete molecular dynamics simulations. This allowed us to retrieve integrative structure models of α-Synuclein dimer structural subpopulations, having different degrees of compactness and binding energies. Interestingly, one of dimers structures is compact, stable, abundant and exhibits partially-exposed β-sheet structures in the N-terminal and non-amyloid component segments. This compact dimer form is also the only one that exhibits interaction distances between hydroxyl groups of tyrosine 39 in the two subunits. We suggest that the high abundance compact dimer form serves as an important α-Synuclein dimeric species and propose different hypotheses as to its function, whether on pathway to aggregation or not