Impact of Phosphorylation on the Physiological Form of Human alpha-Synuclein in Aqueous Solution

Serine 129 can be phosphorylated in pathological inclusions formed by the intrinsically disordered protein human α-synuclein (AS), a key player in Parkinson's disease and other synucleinopathies. Here, molecular simulations provide insight into the structural ensemble of phosphorylated AS. The simulations allow us to suggest that phosphorylation significantly impacts the structural content of the physiological AS conformational ensemble in aqueous solution, as the phosphate group is mostly solvated. The hydrophobic region of AS contains β-hairpin structures, which may increase the propensity of the protein to undergo amyloid formation, as seen in the nonphysiological (nonacetylated) form of the protein in a recent molecular simulation study. Our findings are consistent with existing experimental data with the caveat of the observed limitations of the force field for the phosphorylated moiety.

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Publication Details

Journal
Journal of Chemical Information and Modeling
Published
2024-10-28
DOI
https://doi.org/10.1021/acs.jcim.4c01172
Citations
6
Primary Topic
Parkinson's Disease Mechanisms and Treatments
Type
article
Field-Weighted Citation Impact
2.21

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article

Impact of Phosphorylation on the Physiological Form of Human alpha-Synuclein in Aqueous Solution

Tiago F. Outeiro, Emile De Bruyn, Claudio O. Fernández, Giulia Rossetti et al.
6 citations
Journal of Chemical Information and Modeling
Parkinson's Disease Mechanisms and Treatments
2.21
article

Impact of Phosphorylation on the Physiological Form of Human alpha-Synuclein in Aqueous Solution

Tiago F. Outeiro, Emile De Bruyn, Claudio O. Fernández, Giulia Rossetti, Jörg B. Schulz, Paolo Carloni, Anton Emil Dorn
article en
6 citations

Abstract

Serine 129 can be phosphorylated in pathological inclusions formed by the intrinsically disordered protein human α-synuclein (AS), a key player in Parkinson's disease and other synucleinopathies. Here, molecular simulations provide insight into the structural ensemble of phosphorylated AS. The simulations allow us to suggest that phosphorylation significantly impacts the structural content of the physiological AS conformational ensemble in aqueous solution, as the phosphate group is mostly solvated. The hydrophobic region of AS contains β-hairpin structures, which may increase the propensity of the protein to undergo amyloid formation, as seen in the nonphysiological (nonacetylated) form of the protein in a recent molecular simulation study. Our findings are consistent with existing experimental data with the caveat of the observed limitations of the force field for the phosphorylated moiety.

Journal of Chemical Information and ModelingVol. 64(21)
Forschungszentrum Jülich (DE), National University of Rosario (AR), Universitätsmedizin Göttingen (DE), Jülich Aachen Research Alliance (DE), Max Planck Institute for Multidisciplinary Sciences (DE), University of Duisburg-Essen (DE), University of Göttingen (DE), Newcastle University (GB), RWTH Aachen University (DE)
Helmholtz-Gemeinschaft, Deutsche Forschungsgemeinschaft, Gauss Centre for Supercomputing
Clean water and sanitation
Openalex Percentile: Top 11%
Parkinson's Disease Mechanisms and Treatments
2.21
DOIOpen Access PDFOpenAlex
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