A structural model of toxic amyloid oligomers involved in type 2 diabetes

Amyloid oligomers of the human islet amyloid polypeptide (hIAPP) are a likely cytotoxic species driving β-cell death in type 2 diabetes, but their transient nature has precluded atomic-level structural characterization. We obtained a high-resolution structure of a physiologically relevant hIAPP oligomer. Using 2D IR spectroscopy, we identified three substitutions that slowed aggregation sufficiently for comprehensive 2D/3D NMR analysis while retaining the key wild-type structural features and cytotoxicity. The structural model reveals a dimeric assembly with N-terminal helices and a kink that facilitates an intermolecular β-sheet. The β-sheet spans the famous FGAILS portion of the sequence, helping to explain species-specific diabetes susceptibility and the origin of early-onset familial mutations. The integrated 2D IR/NMR strategy provides a unique approach to obtaining high-resolution structures of amyloid oligomers.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2026-01-26
DOI
https://doi.org/10.1073/pnas.2528103123
Primary Topic
Alzheimer's disease research and treatments
Type
article
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article

A structural model of toxic amyloid oligomers involved in type 2 diabetes

Mark P. Keller, Alexei A. Kananenka, Martin T. Zanni, Caitlyn R. Fields et al.
Proceedings of the National Academy of Sciences
Alzheimer's disease research and treatments
article

A structural model of toxic amyloid oligomers involved in type 2 diabetes

Mark P. Keller, Alexei A. Kananenka, Martin T. Zanni, Caitlyn R. Fields, Harrison J. Esterly, Chad M. Rienstra, Sidney S. Dicke, Kacie L. Rich, Katherine A. Henzler‐Wildman, Alan Attie, Thirupathi Ravula, Owen A. Warmuth, Brynn E. LeMasters, Donald S. Stapleton, Shivani T. Shivani, Nikhil Maroli
article en

Abstract

Amyloid oligomers of the human islet amyloid polypeptide (hIAPP) are a likely cytotoxic species driving β-cell death in type 2 diabetes, but their transient nature has precluded atomic-level structural characterization. We obtained a high-resolution structure of a physiologically relevant hIAPP oligomer. Using 2D IR spectroscopy, we identified three substitutions that slowed aggregation sufficiently for comprehensive 2D/3D NMR analysis while retaining the key wild-type structural features and cytotoxicity. The structural model reveals a dimeric assembly with N-terminal helices and a kink that facilitates an intermolecular β-sheet. The β-sheet spans the famous FGAILS portion of the sequence, helping to explain species-specific diabetes susceptibility and the origin of early-onset familial mutations. The integrated 2D IR/NMR strategy provides a unique approach to obtaining high-resolution structures of amyloid oligomers.

Proceedings of the National Academy of SciencesVol. 123(5)
University of Wisconsin–Madison (US), University of Delaware (US)
Openalex Percentile: Top 78%
Alzheimer's disease research and treatments
DOIOpen Access PDFOpenAlex
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