Abstract:
:The pathological and physiological hallmarks of the protein alpha-synuclein (aS) 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 conformations to structured conformations. Based on aS interactions with aggregation-inhibiting small molecules, an aS variant termed shuffled alpha-synuclein (SaS), wherein the first six pseudorepeats had been rearranged, was introduced. Here, the effects of this rearrangement on misfolding, vesicle binding, and micelle binding are examined in reference to aS and beta-synuclein to study the sequence characteristics underlying these processes. Fibrillization correlates with the distinct clustering of residues with high beta-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 aS and beta-synuclein encounter a distinct helix break, indicating that a more homogeneous distribution of surfactant affinities in SaS prevented the formation of an extensive helix break in the micelle-bound state. By demonstrating the importance of the distribution of beta-sheet propensities and by revealing inhomogeneous aS surfactant affinities, the present study provides novel insights into two central themes of synuclein biology.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Rao JN,Kim YE,Park LS,Ulmer TSdoi
10.1016/j.jmb.2009.05.058subject
Has Abstractpub_date
2009-07-17 00:00:00pages
516-29issue
3eissn
0022-2836issn
1089-8638pii
S0022-2836(09)00628-7journal_volume
390pub_type
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