Effect of Pseudorepeat Rearrangement upon α-Synuclein Misfolding, Vesicle Binding and Micelle Binding

• Published in: Journal of molecular biology 2009-05, Vol.390 (3), p.516-529
• Main Authors: Rao, Jampani Nageswara, Kim, Yujin E., Park, Leena S., Ulmer, Tobias S.
• Format: Article
• Language: English
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2009.05.058

The pathological and physiological hallmarks of the protein α-synuclein are its misfolding into cytotoxic aggregates and its binding to synaptic vesicles, respectively. Both events are mediated by seven 11-residue amphiphilic pseudorepeats and, most generally, involve a transition from intrinsically unstructured to structured conformations. Based upon α-synuclein interactions with aggregation-inhibiting small molecules, a α-synuclein variant termed SaS, wherein the first six pseudorepeats had been rearranged, was introduced. Here, the effects of this rearrangement upon misfolding, vesicle binding and micelle binding are examined in reference to α- and β-synuclein to study the sequence characteristics underlying these processes. Fibrillization correlates with the distinct clustering of residues with high β-sheet propensities, while vesicle affinities depend on the mode of pseudorepeat interchange and loss. In the presence of micelles, the pseudorepeat region of SaS adopts an essentially continuous helix, whereas α- and β-synuclein encounter a distinct helix break, indicating that a more homogeneous distribution of surfactant affinities in SaS prevented the formation of a helix break in the micelle-bound state. By demonstrating the importance of the distribution of β-sheet propensities and by revealing inhomogeneous aS surfactant affinities, the present study provides novel insight into two central themes of synuclein biology.