Proceedings of the National Academy of Sciences of the United States of America · 2026
A structural model of toxic amyloid oligomers involved in type 2 diabetes.
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Shivani Shivani T, LeMasters Brynn E, Ravula Thirupathi, Esterly Harrison J, Maroli Nikhil, Rich Kacie L, Fields Caitlyn R, Dicke Sidney S, Warmuth Owen A, Stapleton Donald S, Keller Mark P, Attie Alan D, Kananenka Alexei A, Henzler-Wildman Katherine A, Rienstra Chad M, Zanni Martin T
Аннотация
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.