Effect of Pseudorepeat Rearrangement on α-Synuclein Misfolding, Vesicle Binding, and Micelle Binding |
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Authors: | Jampani Nageswara Rao |
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Institution: | Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90033, USA Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90033, USA |
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Abstract: | The pathological and physiological hallmarks of the protein α-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 α-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 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 aS and β-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 β-sheet propensities and by revealing inhomogeneous aS surfactant affinities, the present study provides novel insights into two central themes of synuclein biology. |
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Keywords: | aS α-synuclein SaS shuffled α-synuclein SUV small unilamellar vesicle bS β-synuclein SLAS sodium lauroyl sarcosinate LUV large unilamellar vesicle LPPG lyso-1-palmitoyl-phosphotidylglycerol MFR molecular fragment replacement NOE nuclear Overhauser enhancement |
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