A Relationship between the Transient Structure in the Monomeric State and the Aggregation Propensities of α-Synuclein and β-Synuclein

alpha-Synuclein is an intrinsically disordered protein whose aggregation is implicated in Parkinsons disease. A second member of the synuclein family, beta-synuclein, shares significant sequence similarity with alpha-synuclein but is much more resistant to aggregation. beta-Synuclein is missing an 11-residue stretch in the central non-beta-amyloid component region that forms the core of alpha-synuclein amyloid fibrils, yet insertion of these residues into beta-synuclein to produce the beta S-HC construct does not markedly increase the aggregation propensity. To investigate the structural basis of these different behaviors, quantitative nuclear magnetic resonance data, in the form of paramagnetic relaxation enhancement-derived interatomic distances, are combined with molecular dynamics simulations to generate ensembles of structures representative of the solution states of alpha-synuclein, beta-synuclein, and beta S-HC. Comparison of these ensembles reveals that the differing aggregation propensities of beta-synuclein and ?-synuclein are associated with differences in the degree of residual structure in the C-terminus coupled to the shorter separation between the N- and C-termini in beta-synuclein and beta S-HC, making protective intramolecular contacts more likely