A structural model of toxic amyloid oligomers involved in type 2 diabetes
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Shivani T. Shivani
Department of Chemistry, University of Wisconsin
Brynn E. LeMasters
Department of Chemistry, University of Wisconsin
Thirupathi Ravula
Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States
Harrison J. Esterly
Department of Chemistry, University of Wisconsin
Nikhil Maroli
Kacie L. Rich
Department of Chemistry, University of Wisconsin
Caitlyn R. Fields
Department of Chemistry, University of Wisconsin
Sidney S. Dicke
Department of Chemistry, University of Wisconsin
Owen A. Warmuth
Department of Biochemistry, University of Wisconsin
Donald S. Stapleton
Department of Biochemistry, University of Wisconsin
Mark P. Keller
Department of Biochemistry, University of Wisconsin
Alan D. Attie
Department of Biochemistry, University of Wisconsin
Alexei A. Kananenka
Department of Physics and Astronomy
Katherine A. Henzler-Wildman
Department of Biochemistry, University of Wisconsin–Madison
Chad M. Rienstra
Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States
Martin T. Zanni
Department of Chemistry