The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.
NMR of α‐synuclein–polyamine complexes elucidates the mechanism and kinetics of induced aggregation
Open accessAbstract
The aggregation of alpha-synuclein is characteristic of Parkinson's disease (PD) and other neurodegenerative synucleinopathies. The 140-aa protein is natively unstructured; thus, ligands binding to the monomeric form are of therapeutic interest. Biogenic polyamines promote the aggregation of alpha-synuclein and may constitute endogenous agents modulating the pathogenesis of PD. We characterized the complexes of natural and synthetic polyamines with alpha-synuclein by NMR and assigned the binding site to C-terminal residues 109-140. Dissociation constants were derived from chemical shift perturbations. Greater polyamine charge (+2 --> +5) correlated with increased affinity and enhancement of fibrillation, for which we propose a simple kinetic mechanism involving a dimeric nucleation center. According to the analysis, polyamines increase the extent of nucleation by approximately 10(4) and the rate of monomer addition approximately 40-fold. Significant secondary structure is not induced in monomeric alpha-synuclein by polyamines at 15 degrees C. Instead, NMR reveals changes in a region (aa 22-93) far removed from the polyamine binding site and presumed to adopt the beta-sheet conformation characteristic of fibrillar alpha-synuclein. We conclude that the C-terminal domain acts as a regulator of alpha-synuclein aggregation.
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Cites
Protein folding and misfolding
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α-Synuclein is phosphorylated in synucleinopathy lesions
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NACP, A Protein Implicated in Alzheimer's Disease and Learning, Is Natively Unfolded
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Alpha-synuclein and neurodegenerative diseases
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Metal-triggered Structural Transformations, Aggregation, and Fibrillation of Human α-Synuclein
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Evidence for a Partially Folded Intermediate in α-Synuclein Fibril Formation
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Cited by
Gaggelli, E., Kozlowski, H., Valensin, D., & Valensin, G. (2006) · Chemical Reviews · doi:10.1021/cr040410w · Cited by 1,729
α-Synuclein misfolding and Parkinson's disease
Breydo, L., Wu, J. W., & Uversky, V. N. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.10.002 · Cited by 657
Cell Biology and Pathophysiology of α-Synuclein
Burré, J., Sharma, M., & Südhof, T. C. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024091 · Cited by 579
The Synaptic Function of α-Synuclein
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Metadata
- Authors
- Fernández, C. O., Hoyer, W., Zweckstetter, M., Jares‐Erijman, E. A., Subramaniam, V., Griesinger, C., & Jovin, T. M.
- Venue
- The EMBO Journal
- Published
- 2004-04-22
- Volume
- 23
- Issue
- 10
- Pages
- 2039-2046
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- OpenAlex
- W2060745831
- Cited by
- 255
- References
- 40
- FWCI
- 8.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Fernández, C. O., Hoyer, W., Zweckstetter, M., Jares‐Erijman, E. A., Subramaniam, V., Griesinger, C., & Jovin, T. M. (2004). NMR of α‐synuclein–polyamine complexes elucidates the mechanism and kinetics of induced aggregation. The EMBO Journal. https://doi.org/10.1038/sj.emboj.7600211
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