A structural model of toxic amyloid oligomers involved in type 2 diabetes
- Shivani T. Shivani
- Brynn E. LeMasters
- Thirupathi Ravula
- Harrison J. Esterly
- Nikhil Maroli
- Kacie L. Rich
- Caitlyn R. Fields
- Sidney S. Dicke
- Owen A. Warmuth
- Donald S. Stapleton
- Mark P. Keller
- Alan D. Attie
- Alexei A. Kananenka
- Katherine A. Henzler-Wildman
- Chad M. Rienstra
- Martin T. Zanni
2026-01-26
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.