Fibril Structure of Human Islet Amyloid Polypeptide

• Published in: The Journal of biological chemistry Vol. 287; no. 8; pp. 5235 - 5241
• Main Authors: Bedrood, Sahar, Li, Yiyu, Isas, J. Mario, Hegde, Balachandra G., Baxa, Ulrich, Haworth, Ian S., Langen, Ralf
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.02.2012; American Society for Biochemistry and Molecular Biology
• Subjects: alpha-Synuclein - metabolism; Amino Acid Sequence; Amyloid; Cell Membrane - metabolism; Computer Modeling; Electron Paramagnetic Resonance (EPR); Electron Spin Resonance Spectroscopy; Fibril; Helix; Human Islet Amyloid Polypeptide; Humans; Islet Amyloid Polypeptide - chemistry; Islet Amyloid Polypeptide - metabolism; Microscopy, Electron; Molecular Dynamics Simulation; Molecular Sequence Data; Protein Multimerization; Protein Stability; Protein Structure; Protein Structure and Folding; Protein Structure, Secondary; Structural Biology; Human Islet Amyloid Polypeptide; Electron Paramagnetic Resonance (EPR); Computer Modeling; Structural Biology; Helix; Amyloid; Protein Structure; Fibril
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.327817

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. Human islet amyloid polypeptide (hIAPP) fibrils of unknown structure are formed in type 2 diabetes. A hIAPP fibril structure was derived from EPR data, electron microscopy, and computer modeling. The fibril is a left-handed helix that contains hIAPP monomers in a staggered conformation. The results provide the basis for therapeutic prevention of fibril formation and growth.