title: Lipid membranes modulate the structure of islet amyloid polypeptide.
abstract: The 37-residue islet amyloid polypeptide (IAPP) is thought to play an important role in the pathogenesis of type II diabetes. Despite a growing body of evidence implicating membrane interaction in IAPP toxicity, the membrane-bound form has not yet been well characterized. Here we used circular dichroism (CD) and fluorescence spectroscopy to investigate the molecular details of the interaction of IAPP with lipid membranes of varying composition. In the presence of membranes containing negatively charged phosphatidylserine (PS), we observed significant acceleration in the formation of IAPP aggregates. This acceleration is strongly modulated by the PS concentration and ionic strength, and is also observed at physiologically relevant PS concentrations. CD spectra of IAPP obtained immediately after the addition of membranes containing PS revealed features characteristic of an alpha-helical conformation approximately approximately 15-19 residues in length. After a longer incubation with membranes, IAPP gave rise to CD spectra characteristic of a beta-sheet conformation. Taken together, our CD and fluorescence data indicate that conditions that promote weakly stable alpha-helical conformations may promote IAPP aggregation. The potential roles of IAPP-membrane interaction and the novel membrane-bound alpha-helical conformation in IAPP aggregation are discussed.
authors.affiliation: Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, 1501 San Pablo Street, Los Angeles, California 90033, USA.
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* / Q000378:metabolism*; D000818:Animals; D002942:Circular Dichroism; D004795:Enzyme Stability; D006801:Humans; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000737:chemistry*; D007700:Kinetics; D008563:Membrane Lipids / Q000737:chemistry* / Q000378:metabolism*; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013050:Spectrometry, Fluorescence
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D008563:Membrane Lipids