ArticleProceedings of the National Academy of Sciences of the United States of America2020
The role of fibril structure and surface hydrophobicity in secondary nucleation of amyloid fibrils.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed.
- From helices to superhelices through hierarchical assembly across competing pathways.Nature communications · 2026Article
- Noncovalent synthesis of higher-order super-heterostructures from structurally distinct molecular π-systems via secondary nucleation.Nature communications · 2026Article
- Structural defects in amyloid-β fibrils drive secondary nucleation.Nature communications · 2026Article
- General integrated rate law for complex self-assembly reactions reveals the mechanism of amyloid-beta coaggregation.Physical chemistry chemical physics : PCCP · 2025Article
- Design of Tau Aggregation Inhibitors Using Iterative Machine Learning and a Polymorph-Specific Brain-Seeded Fibril Amplification Assay.Journal of the American Chemical Society · 2025Article
- Investigating Local Sequence-Structural Attributes of Amyloidogenic Light Chain Variable Domains.Proteins · 2025Article
- Massively parallel genetic perturbation suggests the energetic structure of an amyloid-β transition state.Science advances · 2025Article
- Amyloid-forming property of the N-terminal 1-70 residues of human apolipoprotein A-IV.Scientific reports · 2025Article
- The p3 peptides (AβNature communications · 2025Article
- Accelerated Alzheimer's Aβ-42 secondary nucleation chronologically visualized on fibril surfaces.Science advances · 2024Article
- Secondary Nucleation of Aβ Revealed by Single-Molecule and Computational Approaches.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Single-Molecule Fingerprinting Reveals Different Growth Mechanisms in Seed Amplification Assays for Different Polymorphs of α-Synuclein Fibrils.ACS chemical neuroscience · 2024Article
- Modulation of Alzheimer's Disease Aβ40 Fibril Polymorphism by the Small Heat Shock Protein αB-Crystallin.Journal of the American Chemical Society · 2024Article
- CoVAMPnet: Comparative Markov State Analysis for Studying Effects of Drug Candidates on Disordered Biomolecules.JACS Au · 2024Article
- Structural characterization of E22G AβPhysical chemistry chemical physics : PCCP · 2024Article
- Self-replication of AProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Single-domain magnetic particles with motion behavior under electromagnetic AC and DC fields are a fatal cargo in Metropolitan Mexico City pediatric and young adult early Alzheimer, Parkinson, frontotemporal lobar degeneration and amyotrophic lateral sclerosis and in ALS patients.Frontiers in human neuroscience · 2024Article
- Mechanisms and pathology of protein misfolding and aggregation.Nature reviews. Molecular cell biology · 2023Review
- Amyloidogenic 60-71 deletion/ValThr insertion mutation of apolipoprotein A-I generates a new aggregation-prone segment that promotes nucleation through entropic effects.Scientific reports · 2023Article
- The Double-Layered Structure of Amyloid-β Assemblage on GM1-Containing Membranes Catalytically Promotes Fibrillization.ACS chemical neuroscience · 2023Article
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Crystals, nanoparticles, and fibrils catalyze the generation of new aggregates on their surface from the same type of monomeric building blocks as the parent assemblies. This secondary nucleation process can be many orders of magnitude faster than primary nucleation. In the case of amyloid fibrils associated with Alzheimer's disease, this process leads to the multiplication and propagation of aggregates, whereby short-lived oligomeric intermediates cause neurotoxicity. Understanding the catalytic activity is a fundamental goal in elucidating the molecular mechanisms of Alzheimer's and associated diseases. Here we explore the role of fibril structure and hydrophobicity by asking whether the V18, A21, V40, and A42 side chains which are exposed on the Aβ42 fibril surface as continuous hydrophobic patches play a role in secondary nucleation. Single, double, and quadruple serine substitutions were made. Kinetic analyses of aggregation data at multiple monomer concentrations reveal that all seven mutants retain the dominance of secondary nucleation as the main mechanism of fibril proliferation. This finding highlights the generality of secondary nucleation and its independence of the detailed molecular structure. Cryo-electron micrographs reveal that the V18S substitution causes fibrils to adopt a distinct morphology with longer twist distance than variants lacking this substitution. Self- and cross-seeding data show that surface catalysis is only efficient between peptides of identical morphology, indicating a templating role of secondary nucleation with structural conversion at the fibril surface. Our findings thus provide clear evidence that the propagation of amyloid fibril strains is possible even in systems dominated by secondary nucleation rather than fragmentation.
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