Effect of pseudorepeat rearrangement on alpha-synuclein misfolding, vesicle binding, and micelle binding.
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.
Rao
Jampani Nageswara
JN
Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, 90033, USA.
Kim
Yujin E
YE
Park
Leena S
LS
Ulmer
Tobias S
TS
D032621:DNA Shuffling; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D011995:Recombination, Genetic; D020449:Repetitive Sequences, Amino Acid / Q000235:genetics*; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D008823:Micelles; D051844:alpha-Synuclein