ArticleJournal of molecular biology2012
Sensitivity of amyloid formation by human islet amyloid polypeptide to mutations at residue 20.
Article in Journal of molecular biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 87 citations in OpenAlex.
- Massively parallel quantification of mutational impact on IAPP amyloid formation.Nature communications · 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
- O-glycosylated peptides curtail the aggregation and toxicity of human islet amyloid polypeptide.Communications biology · 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
- Peptidylglycine alpha-amidating monooxygenase is important in mice for beta-cell cilia formation and insulin secretion but promotes diabetes risk through beta-cell independent mechanisms.Molecular metabolism · 2025Article
- Understanding the structural dynamics of human islet amyloid polypeptide: Advancements in and applications of ion-mobility mass spectrometry.Biophysical chemistry · 2024Review
- Article
- Determination of the Structure and Dynamics of the Fuzzy Coat of an Amyloid Fibril of IAPP Using Cryo-Electron Microscopy.Biochemistry · 2023Article
- Analysis of Sheep and Goat IAPP Provides Insight into IAPP Amyloidogenicity and Cytotoxicity.Biochemistry · 2022Article
- Molecular insights into the oligomerization dynamics and conformations of amyloidogenic and non-amyloidogenic amylin from discrete molecular dynamics simulations.Physical chemistry chemical physics : PCCP · 2022Article
- Linking hIAPP misfolding and aggregation with type 2 diabetes mellitus: a structural perspective.Bioscience reports · 2022Review
- Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly.Nature communications · 2022Article
- Molecular Mechanisms of Amylin Turnover, Misfolding and Toxicity in the Pancreas.Molecules (Basel, Switzerland) · 2022Review
- Cryo-EM structures of hIAPP fibrils seeded by patient-extracted fibrils reveal new polymorphs and conserved fibril cores.Nature structural & molecular biology · 2021Article
- Microcanonical insights into the physicochemical stability of the coformulation of insulin with amylin analogues.Journal of molecular modeling · 2021Article
- Cryo-EM structure and inhibitor design of human IAPP (amylin) fibrils.Nature structural & molecular biology · 2020Article
- Cryo-EM structure of islet amyloid polypeptide fibrils reveals similarities with amyloid-β fibrils.Nature structural & molecular biology · 2020Article
- Analysis of Prairie Vole Amylin Reveals the Importance of the N-Terminus and Residue 22 in Amyloidogenicity and Cytotoxicity.Biochemistry · 2020Article
- Differential effects of serine side chain interactions in amyloid formation by islet amyloid polypeptide.Protein science : a publication of the Protein Society · 2020Article
- Amyloidogenicity and cytotoxicity of des-Lys-1 human amylin provides insight into amylin self-assembly and highlights the difficulties of defining amyloidogenicity.Protein engineering, design & selection : PEDS · 2019Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Islet amyloid polypeptide (IAPP, amylin) is responsible for amyloid formation in type 2 diabetes and in islet cell transplants. The only known natural mutation found in mature human IAPP is a Ser20-to-Gly missense mutation, found with small frequency in Chinese and Japanese populations. The mutation appears to be associated with increased risk of early-onset type 2 diabetes. Early measurements in the presence of organic co-solvents showed that S20G-IAPP formed amyloid more quickly than the wild type. We confirm that the mutant accelerates amyloid formation under a range of conditions including in the absence of co-solvents. Ser20 adopts a normal backbone geometry, and the side chain makes no steric clashes in models of IAPP amyloid fibers, suggesting that the increased rate of amyloid formation by the mutant does not result from the relief of steric incompatibility in the fiber state. Transmission electronic microscopy, circular dichroism, and seeding studies were used to probe the structure of the resulting fibers. The S20G-IAPP peptide is toxic to cultured rat INS-1 (transformed rat insulinoma-1) β-cells. The sensitivity of amyloid formation to the identity of residue 20 was exploited to design a variant that is much slower to aggregate and that inhibits amyloid formation by wild-type IAPP. An S20K mutant forms amyloid with an 18-fold longer lag phase in homogeneous solution. Thioflavin T binding assays, together with experiments using a p-cyanophenylalanine (p-cyanoPhe) variant of human IAPP, show that the designed S20K mutant inhibits amyloid formation by human IAPP. The experiments illustrate how p-cyanoPhe can be exploited to monitor amyloid formation even in the presence of other amyloidogenic proteins.
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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.