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

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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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Autores principales: Fernández, C.O., Hoyer, W., Zweckstetter, M., Jares-Erijman, E.A., Subramaniam, V., Griesinger, C., Jovin, T.M.
Formato: Artículo publishedVersion
Lenguaje:Inglés
Publicado: 2004
Materias:
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
Acceso en línea:http://hdl.handle.net/20.500.12110/paper_02614189_v23_n10_p2039_Fernandez
Aporte de:
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires
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spelling paperaa:paper_02614189_v23_n10_p2039_Fernandez2023-06-12T16:47:09Z NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation EMBO J. 2004;23(10):2039-2046 Fernández, C.O. Hoyer, W. Zweckstetter, M. Jares-Erijman, E.A. Subramaniam, V. Griesinger, C. Jovin, T.M. 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 info:eu-repo/semantics/article info:ar-repo/semantics/artículo info:eu-repo/semantics/publishedVersion application/pdf eng info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar 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)
language Inglés
orig_language_str_mv eng
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
Fernández, C.O.
Hoyer, W.
Zweckstetter, M.
Jares-Erijman, E.A.
Subramaniam, V.
Griesinger, C.
Jovin, T.M.
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.
format Artículo
Artículo
publishedVersion
author Fernández, C.O.
Hoyer, W.
Zweckstetter, M.
Jares-Erijman, E.A.
Subramaniam, V.
Griesinger, C.
Jovin, T.M.
author_facet Fernández, C.O.
Hoyer, W.
Zweckstetter, M.
Jares-Erijman, E.A.
Subramaniam, V.
Griesinger, C.
Jovin, T.M.
author_sort Fernández, C.O.
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 http://hdl.handle.net/20.500.12110/paper_02614189_v23_n10_p2039_Fernandez
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