title: Fibril structure of human islet amyloid polypeptide.
abstract: Misfolding and amyloid fibril formation by human islet amyloid polypeptide (hIAPP) are thought to be important in the pathogenesis of type 2 diabetes, but the structures of the misfolded forms remain poorly understood. Here we developed an approach that combines site-directed spin labeling with continuous wave and pulsed EPR to investigate local secondary structure and to determine the relative orientation of the secondary structure elements with respect to each other. These data indicated that individual hIAPP molecules take up a hairpin fold within the fibril. This fold contains two β-strands that are much farther apart than expected from previous models. Atomistic structural models were obtained using computational refinement with EPR data as constraints. The resulting family of structures exhibited a left-handed helical twist, in agreement with the twisted morphology observed by electron microscopy. The fibril protofilaments contain stacked hIAPP monomers that form opposing β-sheets that twist around each other. The two β-strands of the monomer adopt out-of-plane positions and are staggered by about three peptide layers (∼15 Å). These results provide a mechanism for hIAPP fibril formation and could explain the remarkable stability of the fibrils. Thus, the structural model serves as a starting point for understanding and preventing hIAPP misfolding.
authors.affiliation: Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Sahar
authors.initials: S
authors.lastname: Bedrood
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Li
authors.forename: J Mario
authors.initials: JM
authors.lastname: Isas
authors.forename: Balachandra G
authors.initials: BG
authors.lastname: Hegde
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baxa
authors.forename: Ian S
authors.initials: IS
authors.lastname: Haworth
authors.forename: Ralf
authors.initials: R
authors.lastname: Langen
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000378:metabolism; D008854:Microscopy, Electron; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D058228:Islet Amyloid Polypeptide; D051844:alpha-Synuclein