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

Fernández, Claudio O. and Hoyer, Wolfgang and Zweckstetter, Markus and Jares-Erijman, Elizabeth A. and Subramaniam, Vinod and Griesinger, Christian and Jovin, Thomas M. (2004) NMR of α-synuclein–polyamine complexes elucidates the mechanism and kinetics of induced aggregation. EMBO Journal, 23 (10). pp. 2039-2046. ISSN 0261-4189

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Abstract:	The aggregation of α-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 α-synuclein and may constitute endogenous agents modulating the pathogenesis of PD. We characterized the complexes of natural and synthetic polyamines with α-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 ~ $10^4$ and the rate of monomer addition ~40-fold. Significant secondary structure is not induced in monomeric α-synuclein by polyamines at 15°C. Instead, NMR reveals changes in a region (aa 22–93) far removed from the polyamine binding site and presumed to adopt the β-sheet conformation characteristic of fibrillar α-synuclein. We conclude that the C-terminal domain acts as a regulator of α-synuclein aggregation.
Item Type:	Article
Copyright:	© 2004 European Molecular Biology Organization
Faculty:	Science and Technology (TNW)
Research Group:	Nano-Biophysics (NBP)
Link to this item:	http://purl.utwente.nl/publications/80748
Official URL:	http://dx.doi.org/10.1038/sj.emboj.7600211
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