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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 ∼104 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.

Registro:

Documento: Artículo
Título:NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation
Autor:Fernández, C.O.; Hoyer, W.; Zweckstetter, M.; Jares-Erijman, E.A.; Subramaniam, V.; Griesinger, C.; Jovin, T.M.
Filiación:LANAIS RMN 300, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Buenos Aires, Argentina
Department of Molecular Biology, Max Planck Inst. for Biophys. Chem., Göttingen, Germany
Dept. of NMR-based Struct. Biology, Max Planck Inst. for Biophys. Chem., Göttingen, Germany
Departamento de Quimica Organica, Fac. de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Biophysical Engineering Group, Faculty of Science and Technology, University of Twente, Enschede, Netherlands
Lab. Nac. de Resonancia Magnetica, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Buenos Aires, Argentina
Department of Molecular Biology, Max Planck Inst. for Biophys. Chem., Am Fassberg 11, 37077 Göttingen, Germany
Palabras clave:Amyloid; Fibrillation; Parkinson's disease; Spermine; alpha synuclein; amyloid; polyamine; spermine; article; binding site; carboxy terminal sequence; dissociation constant; ligand binding; molecular dynamics; Parkinson disease; priority journal; protein aggregation; protein folding; alpha-Synuclein; Amino Acid Sequence; Binding Sites; Fluorescent Dyes; Humans; Molecular Sequence Data; Molecular Structure; Nerve Tissue Proteins; Nuclear Magnetic Resonance, Biomolecular; Parkinson Disease; Polyamines; Protein Structure, Secondary; Synucleins; Thiazoles
Año:2004
Volumen:23
Número:10
Página de inicio:2039
Página de fin:2046
DOI: http://dx.doi.org/10.1038/sj.emboj.7600211
Título revista:EMBO Journal
Título revista abreviado:EMBO J.
ISSN:02614189
CODEN:EMJOD
CAS:alpha synuclein, 154040-18-3; amyloid, 11061-24-8; spermine, 306-67-2, 71-44-3; alpha-Synuclein; Fluorescent Dyes; Nerve Tissue Proteins; Polyamines; SNCA protein, human; Synucleins; Thiazoles; thioflavin T, 2390-54-7
PDF:https://bibliotecadigital.exactas.uba.ar/download/paper/paper_02614189_v23_n10_p2039_Fernandez.pdf
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02614189_v23_n10_p2039_Fernandez

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Citas:

---------- APA ----------
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. EMBO Journal, 23(10), 2039-2046.
http://dx.doi.org/10.1038/sj.emboj.7600211
---------- CHICAGO ----------
Fernández, C.O., Hoyer, W., Zweckstetter, M., Jares-Erijman, E.A., Subramaniam, V., Griesinger, C., et al. "NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation" . EMBO Journal 23, no. 10 (2004) : 2039-2046.
http://dx.doi.org/10.1038/sj.emboj.7600211
---------- MLA ----------
Fernández, C.O., Hoyer, W., Zweckstetter, M., Jares-Erijman, E.A., Subramaniam, V., Griesinger, C., et al. "NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation" . EMBO Journal, vol. 23, no. 10, 2004, pp. 2039-2046.
http://dx.doi.org/10.1038/sj.emboj.7600211
---------- VANCOUVER ----------
Fernández, C.O., Hoyer, W., Zweckstetter, M., Jares-Erijman, E.A., Subramaniam, V., Griesinger, C., et al. NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation. EMBO J. 2004;23(10):2039-2046.
http://dx.doi.org/10.1038/sj.emboj.7600211