ArticleFrontiers in molecular biosciences2021
Surface-Catalyzed Secondary Nucleation Dominates the Generation of Toxic IAPP Aggregates.
Article in Frontiers in molecular biosciences, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 40 citations in OpenAlex.
- Fine-Tuning hIAPP Amyloidogenesis: Probing Molecular Mechanisms via Fluorinated Core Substitutions.ACS bio & med chem Au · 2026Article
- Noncovalent synthesis of higher-order super-heterostructures from structurally distinct molecular π-systems via secondary nucleation.Nature communications · 2026Article
- Transient Interactions of α-Synuclein N- and C-Termini.ACS chemical neuroscience · 2026Article
- Rapid elongation drives the exceptionally fast aggregation of the most common localized human amyloid medin.Communications chemistry · 2026Article
- Structural and morphological dynamics of "on-path" and "off-path" oligomers of human islet amyloid polypeptide.Protein science : a publication of the Protein Society · 2026Article
- Massively parallel quantification of mutational impact on IAPP amyloid formation.Nature communications · 2026Article
- Molecular Mechanisms of Islet Amyloid Polypeptide Aggregation: Towards Chemical Strategies to Prevent Amyloid Formation and to Design Non-Aggregating Peptide Therapeutics.International journal of molecular sciences · 2026Review
- Structural defects in amyloid-β fibrils drive secondary nucleation.Nature communications · 2026Article
- Monomer binding modes of small molecules that modulate the kinetics of hIAPP amyloid formation.bioRxiv : the preprint server for biology · 2025Article
- The Structure of Human IAPP Fibrils Reflects Membrane and pH Conditions.Journal of the American Chemical Society · 2025Article
- Kinetic Steering of Amyloid Formation and Polymorphism by Canagliflozin, a Type-2 Diabetes Drug.Journal of the American Chemical Society · 2025Article
- On the reversibility of amyloid fibril formation.Biophysics reviews · 2025Review
- Understanding the structural dynamics of human islet amyloid polypeptide: Advancements in and applications of ion-mobility mass spectrometry.Biophysical chemistry · 2024Review
- Mitigating diabetes associated with reactive oxygen species (ROS) and protein aggregation through pharmacological interventions.RSC advances · 2024Review
- Noncovalent synthesis of homo and hetero-architectures of supramolecular polymers via secondary nucleation.Nature communications · 2024Article
- Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases.Molecular neurodegeneration · 2024Review
- Article
- A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models.Nature communications · 2023Article
- Determination of the Structure and Dynamics of the Fuzzy Coat of an Amyloid Fibril of IAPP Using Cryo-Electron Microscopy.Biochemistry · 2023Article
- Global analysis of kinetics reveals the role of secondary nucleation in recombinant spider silk self-assembly.Protein science : a publication of the Protein Society · 2023Article
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The aggregation of the human islet amyloid polypeptide (IAPP) is associated with diabetes type II. A quantitative understanding of this connection at the molecular level requires that the aggregation mechanism of IAPP is resolved in terms of the underlying microscopic steps. Here we have systematically studied recombinant IAPP, with amidated C-terminus in oxidised form with a disulphide bond between residues 3 and 7, using thioflavin T fluorescence to monitor the formation of amyloid fibrils as a function of time and IAPP concentration. We used global kinetic analyses to connect the macroscopic measurements of aggregation to the microscopic mechanisms, and show that the generation of new aggregates is dominated by the secondary nucleation of monomers on the fibril surface. We then exposed insulinoma cells to aliquots extracted from different time points of the aggregation process, finding the highest toxicity at the midpoint of the reaction, when the secondary nucleation rate reaches its maximum. These results identify IAPP oligomers as the most cytotoxic species generated during IAPP aggregation, and suggest that compounds that target secondary nucleation of IAPP could be most effective as therapeutic candidates for diabetes type II.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.