Name
Title | ||
|---|---|---|
Comprehensive Structural And Thermodynamic Analysis Of Prefibrillar Wt Alpha-Synuclein And Its G51d, E46k, And A53t Mutants By A Combination Of Small-Angle X-Ray Scattering And Variational Bayesian Weighting |
Abstract | ||
|---|---|---|
The in solution synchrotron small-angle X-ray scattering SAXS technique has been used to investigate an intrinsically disordered protein (IDP) related to Parkinson's disease, the alpha-synuclein (alpha-syn), in prefibrillar diluted conditions. SAXS experiments have been performed as a function of temperature and concentration on the wild type (WT) and on the three pathogenic mutants G51D, E46K, and A53T. To identify the conformers that populate WT alpha-syn and the pathogenic mutants in prefibrillar conditions, scattering data have been analyzed by a new variational bayesian weighting method (VBWSAS) based on an ensemble of conformers, which includes unfolded monomers, trimers, and tetramers, both in helical-rich and strand-rich forms. The developed VBWSAS method uses a thermodynamic scheme to account for temperature and concentration effects and considers long-range protein-protein interactions in the framework of the random phase approximation. The global analysis of the whole set of data indicates that WT alpha-syn is mostly present as unfolded monomers and trimers (helical-rich trimers at low T and strand-rich trimers at high T), but not tetramers, as previously derived by several studies. On the contrary, different conformer combinations characterize mutants. In the a-syn G51D mutant, the most abundant aggregates at all the temperatures are strand-rich tetramers. Strand-rich tetramers are also the predominant forms in the A53T mutant, but their weight decreases with temperature. Only monomeric conformers, with a preference for the ones with the smallest sizes, are present in the E46K mutant. The derived conformational behavior then suggests a different availability of species prone to aggregate, depending on mutation, temperature, and concentration and accounting for the different neurotoxicity of alpha-syn variants. Indeed, this approach may be of pivotal importance to describe conformational and aggregational properties of other IDPs. |
Year | DOI | Venue |
|---|---|---|
2020 | 10.1021/acs.jcim.0c00807 | JOURNAL OF CHEMICAL INFORMATION AND MODELING |
DocType | Volume | Issue |
Journal | 60 | 10 |
ISSN | Citations | PageRank |
1549-9596 | 0 | 0.34 |
References | Authors | |
0 | 7 | |
Name | Order | Citations | PageRank |
|---|---|---|---|
| Paolo Moretti | 1 | 0 | 0.34 |
| Paolo Mariani | 2 | 0 | 0.34 |
| Maria Grazia Ortore | 3 | 0 | 0.34 |
| Nicoletta Plotegher | 4 | 0 | 0.34 |
| Luigi Bubacco | 5 | 0 | 0.34 |
| Mariano Beltramini | 6 | 0 | 0.34 |
| Francesco Spinozzi | 7 | 0 | 0.34 |