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

• Autores: Fernández, C.O.; Hoyer, W.; Zweckstetter, M.; Jares-Erijman, E.A.; Subramaniam, V.; Griesinger, C.; Jovin, T.M.
• Año de publicación: 2004
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: EMBO J. 2004;23(10):2039-2046
• Materia: 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
• Institución: Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales

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.
Fil:Jares-Erijman, E.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.