title: Structures of rat and human islet amyloid polypeptide IAPP(1-19) in micelles by NMR spectroscopy.
abstract: Disruption of the cellular membrane by the amyloidogenic peptide IAPP (or amylin) has been implicated in beta-cell death during type 2 diabetes. While the structure of the mostly inert fibrillar form of IAPP has been investigated, the structural details of the highly toxic prefibrillar membrane-bound states of IAPP have been elusive. A recent study showed that a fragment of IAPP (residues 1-19) induces membrane disruption to a similar extent as the full-length peptide. However, unlike the full-length IAPP peptide, IAPP(1-19) is conformationally stable in an alpha-helical conformation when bound to the membrane. In vivo and in vitro measurements of membrane disruption indicate the rat version of IAPP(1-19), despite differing from hIAPP(1-19) by the single substitution of Arg18 for His18, is significantly less toxic than hIAPP(1-19), in agreement with the low toxicity of the full-length rat IAPP peptide. To investigate the origin of this difference at the atomic level, we have solved the structures of the human and rat IAPP(1-19) peptides in DPC micelles. While both rat and human IAPP(1-19) fold into similar mostly alpha-helical structures in micelles, paramagnetic quenching NMR experiments indicate a significant difference in the membrane orientation of hIAPP(1-19) and rIAPP(1-19). At pH 7.3, the more toxic hIAPP(1-19) peptide is buried deeper within the micelle, while the less toxic rIAPP(1-19) peptide is located at the surface of the micelle. Deprotonating H18 in hIAPP(1-19) reorients the peptide to the surface of the micelle. This change in orientation is in agreement with the significantly reduced ability of hIAPP(1-19) to cause membrane disruption at pH 6.0. This difference in peptide topology in the membrane may correspond to similar topology differences for the full-length human and rat IAPP peptides, with the toxic human IAPP peptide adopting a transmembrane orientation and the nontoxic rat IAPP peptide bound to the surface of the membrane.
authors.affiliation: Department of Biophysics and Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA.
authors.forename: Ravi Prakash Reddy
authors.initials: RP
authors.lastname: Nanga
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Brender
authors.forename: Jiadi
authors.initials: J
authors.lastname: Xu
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Veglia
authors.forename: Ayyalusamy
authors.initials: A
authors.lastname: Ramamoorthy
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D003902:Detergents / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D058228:Islet Amyloid Polypeptide; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D008958:Models, Molecular; D010713:Phosphatidylcholines / Q000494:pharmacology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D011489:Protein Denaturation / Q000187:drug effects; D017433:Protein Structure, Secondary; D051381:Rats
chemical_list: D000682:Amyloid; D003902:Detergents; D058228:Islet Amyloid Polypeptide; D008823:Micelles; D010713:Phosphatidylcholines; D010767:Phosphorylcholine; C028810:dodecylphosphocholine