Extent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity
| Autor: | Alfonso De Simone, Ioanna Mela, Giuliana Fusco, Frank Sobott, Rani Moons, Jonathan J. Phillips, Anass Chiki, Philippa J. Woodhams, Maria Zacharopoulou, Neeleema Seetaloo, Gabriele S. Kaminski Schierle, Hilal A. Lashuel, Amberley D. Stephens |
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| Přispěvatelé: | Stephens, Amberley D [0000-0002-7303-6392], Schierle, Gabriele S Kaminski [0000-0002-1843-2202], Apollo - University of Cambridge Repository, Stephens, A. D., Zacharopoulou, M., Moons, R., Fusco, G., Seetaloo, N., Chiki, A., Woodhams, P. J., Mela, I., Lashuel, H. A., Phillips, J. J., De Simone, A., Sobott, F., Schierle, G. S. K., Stephens, Amberley D. [0000-0002-7303-6392], Schierle, Gabriele S. Kaminski [0000-0002-1843-2202] |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
binding Protein Conformation Parkinson's disease Proton Magnetic Resonance Spectroscopy 692/699/375/365/1718 General Physics and Astronomy Sequence (biology) Protein aggregation 631/45/535/878 chemistry.chemical_compound 0302 clinical medicine Protein structure Mutant Protein Phosphorylation lcsh:Science health care economics and organizations Multidisciplinary dynamics 3. Good health Monomer 140/131 alpha-Synuclein 631/57/2269 Engineering sciences. Technology 631/1647/296 Human Science General Biochemistry Genetics and Molecular Biology Article 82/80 03 medical and health sciences Protein Aggregates Structure-Activity Relationship NMR spectroscopy Structure–activity relationship Humans Benzothiazoles fibrillation 82/83 Alpha-synuclein wild-type Kinetic Intrinsically disordered proteins Mass spectrometry 82/58 Wild type General Chemistry Benzothiazole proteins Kinetics 030104 developmental biology chemistry parkinson Mutation Biophysics residual structure Calcium Mutant Proteins lcsh:Q heterogeneity 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-15 (2020) Nature communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-020-16564-3 |
| Popis: | As an intrinsically disordered protein, monomeric alpha-synuclein (aSyn) occupies a large conformational space. Certain conformations lead to aggregation prone and non-aggregation prone intermediates, but identifying these within the dynamic ensemble of monomeric conformations is difficult. Herein, we used the biologically relevant calcium ion to investigate the conformation of monomeric aSyn in relation to its aggregation propensity. We observe that the more exposed the N-terminus and the beginning of the NAC region of aSyn are, the more aggregation prone monomeric aSyn conformations become. Solvent exposure of the N-terminus of aSyn occurs upon release of C-terminus interactions when calcium binds, but the level of exposure and aSyn’s aggregation propensity is sequence and post translational modification dependent. Identifying aggregation prone conformations of monomeric aSyn and the environmental conditions they form under will allow us to design new therapeutics targeted to the monomeric protein. In Parkinson’s disease (PD) the monomeric protein alpha-synuclein (aSyn) misfolds and aggregates into insoluble fibrils. Here the authors use NMR measurements and hydrogen–deuterium exchange mass spectrometry and find that the more solvent exposed the N-terminus of aSyn is, the more aggregation prone its conformation becomes, and further show how PD mutations and post translational modifications influence the extent of the N-terminus solvent exposure. |
| Databáze: | OpenAIRE |
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