title: Structure of alpha-helical membrane-bound human islet amyloid polypeptide and its implications for membrane-mediated misfolding.
abstract: Human islet amyloid polypeptide (hIAPP) misfolding is thought to play an important role in the pathogenesis of type II diabetes mellitus. It has recently been shown that membranes can catalyze the misfolding of hIAPP via an alpha-helical intermediate of unknown structure. To better understand the mechanism of membrane-mediated misfolding, we used site-directed spin labeling and EPR spectroscopy to generate a three-dimensional structural model of this membrane-bound form. We find that hIAPP forms a single alpha-helix encompassing residues 9-22. The helix is flanked by N- and C-terminal regions that do not take up a clearly detectable secondary structure and are less ordered. Residues 21 and 22 are located in a transitional region between the alpha-helical structure and C terminus and exhibit significant mobility. The alpha-helical structure presented here has important implications for membrane-mediated aggregation. Anchoring hIAPP to the membrane not only increases the local concentration but also reduces the encounter between peptides to essentially a two-dimensional process. It is significant to note that the alpha-helical membrane-bound form leaves much of an important amyloidogenic region of hIAPP (residues 20-29) exposed for misfolding. Misfolding of this and other regions is likely further aided by the low dielectric environment near the membrane that is known to promote secondary structure formation. Based upon these considerations, a structural model for membrane-mediated aggregation is discussed.
authors.affiliation: Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Melania
authors.initials: M
authors.lastname: Apostolidou
authors.forename: Sajith A
authors.initials: SA
authors.lastname: Jayasinghe
authors.forename: Ralf
authors.initials: R
authors.lastname: Langen
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013113:Spin Labels
chemical_list: D000682:Amyloid; D010455:Peptides; D013113:Spin Labels