Conformational ensemble of human α-synuclein physiological form predicted by molecular simulations

Rossetti, Giulia; Musiani, Francesco; Abad, Etna; Dibenedetto, Domenica; Mouhib, Halima; Fernandez, Claudio O.; Carloni, Paolo

doi:10.1039/c5cp04549e

Cited by 33 publications

(42 citation statements)

References 52 publications

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“…[32,42] Quantitative agreement in the relative amounts, instead, is more difficult to test because accurate simulations of disordered conformational ensembles are highly challenging. [43][44][45] Nevertheless, comparison with experimental solution methods has shown good agreement with species distributions obtained by native-MS for unfolding transitions of globular proteins. [41,46] The role of SASA during protein electrospray can be rationalized by the results of computational simulations of protein structures under electrospray conditions.…”

Section: Doi: 101002/pmic201800060mentioning

confidence: 77%

Conformational Characterization and Classification of Intrinsically Disordered Proteins by Native Mass Spectrometry and Charge‐State Distribution Analysis

et al. 2018

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Intrinsically disordered proteins (IDPs) are systematically under‐represented in structural proteomics studies. Their structural characterization implies description of the dynamic conformational ensembles populated by these polymers in solution, posing major challenges to biophysical methods. “Native” MS (native‐MS) has emerged as a central tool in this field, conjugating the unique MS analytical power with structurally meaningful descriptors, like solvent‐accessible surface area (SASA) and collisional cross section (CCS). This review summarizes recently published papers comparing native‐MS and solution methods, with a focus on charge‐state‐distribution (CSD) analysis for IDP conformational analysis. The results point to substantial agreement, supporting structural interpretation of native‐MS spectra of IDPs. The discussion is integrated with data from our group on “synthetic” IDPs, obtained by reduction and alkylation of natively folded proteins, whose fold is stabilized by disulfide bridges. Finally, an MS‐based compaction index (CI) is introduced, evaluating SASA with reference to globular and fully disorder proteins. Such a parameter can be calculated for single conformers or the whole conformational ensemble, offering a continuous index for IDP comparison and classification.

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Section: Doi: 101002/pmic201800060mentioning

confidence: 77%

Conformational Characterization and Classification of Intrinsically Disordered Proteins by Native Mass Spectrometry and Charge‐State Distribution Analysis

et al. 2018

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“…Because the histidine 50 (H50) residue is key for anchoring Cu 2+ binding to aSyn, the results suggested that the critical step for the effects observed in Cu 2+ -mediated aSyn aggregation might be the formation aSyn-Cu 2+ complexes at this site. In vitro NMR (28) and electron paramagnetic resonance (26,29) experiments have suggested that the ion binds in a square planar or tetrahedral distorted geometry, involving 2 or 3 N ligands and 2 or 1 O ligands, respectively (29)(30)(31). Models A and B (SI Appendix, SI Molecular Simulations) have been proposed in the literature (28,29,32).…”

Section: Resultsmentioning

confidence: 99%

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Villar‐Piqué

Fonseca

Sant’Anna

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.α-synuclein | copper | H50Q mutation | inclusions | protein aggregation

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“…Although the CD spectroscopy showed a characteristic negative peak at ~ 218 nm for both acetylated-S and WT-S fibrils, the acetylated-S fibrils had slightly higher β sheet content (Figure 5.5C). Similar differences in calculated CD spectra have been recently reported for S with and without N-terminal acetylation by MD simulations 268 . The mean fibril length of WT-S was ~ 6 fold higher than the acetylated-S fibril length (Figure 5.6).…”

Section: Resultssupporting

confidence: 88%

The many faces of alpha synuclein: from phospholipid bilayer interactions to amyloid aggregation

Iyer¹

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Conformational ensemble of human α-synuclein physiological form predicted by molecular simulations

Cited by 33 publications

References 52 publications

Conformational Characterization and Classification of Intrinsically Disordered Proteins by Native Mass Spectrometry and Charge‐State Distribution Analysis

Conformational Characterization and Classification of Intrinsically Disordered Proteins by Native Mass Spectrometry and Charge‐State Distribution Analysis

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

The many faces of alpha synuclein: from phospholipid bilayer interactions to amyloid aggregation

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