NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation
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-synu...
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2004
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02614189_v23_n10_p2039_Fernandez http://hdl.handle.net/20.500.12110/paper_02614189_v23_n10_p2039_Fernandez |
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paper:paper_02614189_v23_n10_p2039_Fernandez2023-06-08T15:22:45Z NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation Jares, Elizabeth Andrea 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 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. 2004 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02614189_v23_n10_p2039_Fernandez http://hdl.handle.net/20.500.12110/paper_02614189_v23_n10_p2039_Fernandez |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Jares, Elizabeth Andrea NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation |
| topic_facet |
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 |
| description |
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. |
| author |
Jares, Elizabeth Andrea |
| author_facet |
Jares, Elizabeth Andrea |
| author_sort |
Jares, Elizabeth Andrea |
| title |
NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation |
| title_short |
NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation |
| title_full |
NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation |
| title_fullStr |
NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation |
| title_full_unstemmed |
NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation |
| title_sort |
nmr of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation |
| publishDate |
2004 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02614189_v23_n10_p2039_Fernandez http://hdl.handle.net/20.500.12110/paper_02614189_v23_n10_p2039_Fernandez |
| work_keys_str_mv |
AT jareselizabethandrea nmrofasynucleinpolyaminecomplexeselucidatesthemechanismandkineticsofinducedaggregation |
| _version_ |
1768546251226218496 |