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

MPS-Authors
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Fernandez,  C. O.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Hoyer,  W.
Department of Molecular Biology, MPI for biophysical chemistry, Max Planck Society;

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Zweckstetter,  M.
Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

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Jares-Erijman,  E. A.
Department of Molecular Biology, MPI for biophysical chemistry, Max Planck Society;

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Subramaniam,  V.
Department of Molecular Biology, MPI for biophysical chemistry, Max Planck Society;

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Griesinger,  C.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Jovin,  T. M.
Department of Molecular Biology, MPI for biophysical chemistry, Max Planck Society;

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Citation

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.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0012-EDAD-8
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.