ArticleProceedings of the National Academy of Sciences of the United States of America2013
Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 135 papers.
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Who cites it
135 citing papers in PubMed.
- Fine-Tuning hIAPP Amyloidogenesis: Probing Molecular Mechanisms via Fluorinated Core Substitutions.ACS bio & med chem Au · 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
- Mammals that can develop type 2 diabetes have a similarly structured β-sheet amyloid oligomer.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- A structural model of toxic amyloid oligomers involved in type 2 diabetes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Parallel in-register contact propensity predicts the Amyloidogenicity of ADan and ABri in familial dementias.International journal of biological macromolecules · 2026Article
- Development of Petrelintide: a Potent, Stable, Long-Acting Human Amylin Analogue.Journal of medicinal chemistry · 2025Article
- Advances in Probing Amyloid Heterogeneity Using Vibrational Spectroscopy and Imaging.The journal of physical chemistry. B · 2025Review
- AmyloGram reveals amyloidogenic potential in stroke thrombus proteomes.The Biochemical journal · 2025Article
- Experimental and computational analysis of the basis for accelerated amyloid formation by a disease linked mutant of human islet amyloid polypeptide.Protein science : a publication of the Protein Society · 2025Article
- The role of hydrophobic collapse in cytotoxic and functional amyloid oligomerization.Biophysical journal · 2025Article
- Refining Structural Analysis of Proteins: Automated Methods to Measure Transition Dipole Strength of Single Residues.The journal of physical chemistry. B · 2025Article
- Kinetic Steering of Amyloid Formation and Polymorphism by Canagliflozin, a Type-2 Diabetes Drug.Journal of the American Chemical Society · 2025Article
- Rapid discovery of cyclic peptide protein aggregation inhibitors by continuous selection.Nature chemical biology · 2025Article
- Identifying the Role of Individual Seal IAPP Amino Acids in Inhibiting the Aggregation of Human IAPP.Protein and peptide letters · 2025Article
- Understanding the structural dynamics of human islet amyloid polypeptide: Advancements in and applications of ion-mobility mass spectrometry.Biophysical chemistry · 2024Review
- Suppressing sidechain modes and improving structural resolution for 2D IR spectroscopy via vibrational lifetimes.The Journal of chemical physics · 2024Article
- Zinc and pH modulate the ability of insulin to inhibit aggregation of islet amyloid polypeptide.Communications biology · 2024Article
- Improving cryo-EM grids for amyloid fibrils using interface-active solutions and spectator proteins.Biophysical journal · 2024Article
- Using 2D-IR Spectroscopy to Measure the Structure, Dynamics, and Intermolecular Interactions of Proteins in HAccounts of chemical research · 2024Review
- Biomolecular infrared spectroscopy: making time for dynamics.Chemical science · 2024Review
75 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors.
Funding
Abstract
Amyloid formation is implicated in more than 20 human diseases, yet the mechanism by which fibrils form is not well understood. We use 2D infrared spectroscopy and isotope labeling to monitor the kinetics of fibril formation by human islet amyloid polypeptide (hIAPP or amylin) that is associated with type 2 diabetes. We find that an oligomeric intermediate forms during the lag phase with parallel β-sheet structure in a region that is ultimately a partially disordered loop in the fibril. We confirm the presence of this intermediate, using a set of homologous macrocyclic peptides designed to recognize β-sheets. Mutations and molecular dynamics simulations indicate that the intermediate is on pathway. Disrupting the oligomeric β-sheet to form the partially disordered loop of the fibrils creates a free energy barrier that is the origin of the lag phase during aggregation. These results help rationalize a wide range of previous fragment and mutation studies including mutations in other species that prevent the formation of amyloid plaques.
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