ArticleProceedings of the National Academy of Sciences of the United States of America2021
NMR unveils an N-terminal interaction interface on acetylated-α-synuclein monomers for recruitment to fibrils.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 4 citations in OpenAlex.
- Probing the Energy Landscape of α-Synuclein Amyloid Fibril Formation by Systematic K-to-Q Mutagenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- CPEB3 selectively inhibits α-synuclein aggregation without modulating TDP-43 pathology.FEBS letters · 2026Article
- The amplification of α-synuclein amyloid fibrils.Biochemical Society transactions · 2026Review
- Differential effects of α-Synuclein monomers and seeds on the material properties of Tau condensates.bioRxiv : the preprint server for biology · 2026Article
- Transient Interactions of α-Synuclein N- and C-Termini.ACS chemical neuroscience · 2026Article
- Interactions Between Nutraceuticals and α-Synuclein Conformational States: Molecular Mechanisms and Neuroprotective Implications in Parkinson's Disease.International journal of molecular sciences · 2026Review
- Phosphorylation of α‑Synuclein Fibrils at S129 Changes DNAJB1 Binding as Probed by Solid-State NMR.JACS Au · 2026Article
- Surface wetting is a key determinant of α-synuclein condensate maturation.Communications chemistry · 2025Article
- Mapping the Role of Monomer Conformation in the Amyloid Formation of α-Synuclein Splice Variants.Journal of the American Chemical Society · 2025Article
- ZnJournal of the American Chemical Society · 2025Article
- Lipid packing defects are necessary and sufficient for membrane binding of α-synuclein.Communications biology · 2025Article
- Probing the effect of the disordered flank regions on amyloid fibril growth and proliferation.RSC advances · 2025Article
- Lipid Packing Defects are Necessary and Sufficient for Membrane Binding of α-Synuclein.bioRxiv : the preprint server for biology · 2025Article
- Defining essential charged residues in fibril formation of a lysosomal derived N-terminal α-synuclein truncation.Nature communications · 2025Article
- Structural Context Modulates the Conformational Ensemble of the Intrinsically Disordered Amino Terminus of α-Synuclein.Journal of the American Chemical Society · 2025Article
- In cell NMR reveals cells selectively amplify and structurally remodel amyloid fibrils.bioRxiv : the preprint server for biology · 2024Article
- Residues 2 to 7 of α-synuclein regulate amyloid formation via lipid-dependent and lipid-independent pathways.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Modulation of Alzheimer's Disease Aβ40 Fibril Polymorphism by the Small Heat Shock Protein αB-Crystallin.Journal of the American Chemical Society · 2024Article
- Structural Insights into Seeding Mechanisms of hIAPP Fibril Formation.Journal of the American Chemical Society · 2024Article
- A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion.Journal of the American Chemical Society · 2024Article
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Authors and funding
5 authors at 1 institution in 2 countries.
Funding
Abstract
Amyloid fibril formation of α-synuclein (αS) is associated with multiple neurodegenerative diseases, including Parkinson's disease (PD). Growing evidence suggests that progression of PD is linked to cell-to-cell propagation of αS fibrils, which leads to seeding of endogenous intrinsically disordered monomer via templated elongation and secondary nucleation. A molecular understanding of the seeding mechanism and driving interactions is crucial to inhibit progression of amyloid formation. Here, using relaxation-based solution NMR experiments designed to probe large complexes, we probe weak interactions of intrinsically disordered acetylated-αS (Ac-αS) monomers with seeding-competent Ac-αS fibrils and seeding-incompetent off-pathway oligomers to identify Ac-αS monomer residues at the binding interface. Under conditions that favor fibril elongation, we determine that the first 11 N-terminal residues on the monomer form a common binding site for both fibrils and off-pathway oligomers. Additionally, the presence of off-pathway oligomers within a fibril seeding environment suppresses seeded amyloid formation, as observed through thioflavin-T fluorescence experiments. This highlights that off-pathway αS oligomers can act as an auto-inhibitor against αS fibril elongation. Based on these data taken together with previous results, we propose a model in which Ac-αS monomer recruitment to the fibril is driven by interactions between the intrinsically disordered monomer N terminus and the intrinsically disordered flanking regions (IDR) on the fibril surface. We suggest that this monomer recruitment may play a role in the elongation of amyloid fibrils and highlight the potential of the IDRs of the fibril as important therapeutic targets against seeded amyloid formation.
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