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  NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation

Fernandez, C. O., Hoyer, W., Zweckstetter, M., Jares-Erijman, E. A., Subramaniam, V., Griesinger, C., et al. (2004). NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation. EMBO Journal, 23: doi:10.1038/sj.emboj.7600211, pp. 2039-2046. Retrieved from http://www.nature.com/emboj/journal/v23/n10/full/7600211a.html.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0012-EDAD-8 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-0945-C
Genre: Journal Article

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 Creators:
Fernandez, C. O.1, Author              
Hoyer, W.2, Author              
Zweckstetter, M.3, Author              
Jares-Erijman, E. A.2, Author              
Subramaniam, V.2, Author              
Griesinger, C.1, Author              
Jovin, T. M.2, Author              
Affiliations:
1Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
2Department of Molecular Biology, MPI for biophysical chemistry, Max Planck Society, ou_578628              
3Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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Free keywords: amyloid; fibrillation; Parkinson’s disease; spermine
 Abstract: 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 B104 and the rate of monomer addition B40-fold. Significant secondary structure is not induced in monomeric alpha-synuclein by polyamines at 151C. 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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Language(s): eng - English
 Dates: 2004-05-192004-04-22
 Publication Status: Published in print
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Title: EMBO Journal
Source Genre: Journal
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Pages: - Volume / Issue: 23 Sequence Number: doi:10.1038/sj.emboj.7600211 Start / End Page: 2039 - 2046 Identifier: -