title: Probing ion channel activity of human islet amyloid polypeptide (amylin).
abstract: Interactions of human islet amyloid polypeptide (hIAPP or amylin) with the cell membrane are correlated with the dysfunction and death of pancreatic islet β-cells in type II diabetes. Formation of receptor-independent channels by hIAPP in the membrane is regarded as one of the membrane-damaging mechanisms that induce ion homeostasis and toxicity in islet β-cells. Here, we investigate the dynamic structure, ion conductivity, and membrane interactions of hIAPP channels in the DOPC bilayer using molecular modeling and molecular dynamics simulations. We use the NMR-derived β-strand-turn-β-strand motif as a building block to computationally construct a series of annular-like hIAPP structures with different sizes and topologies. In the simulated lipid environments, the channels lose their initial continuous β-sheet network and break into oligomeric subunits, which are still loosely associated to form heterogeneous channel conformations. The channels' shapes, morphologies and dimensions are compatible with the doughnut-like images obtained by atomic force microscopy, and with those of modeled channels for Aβ, the β(2)-microglobulin-derived K3 peptides, and the β-hairpin-based channels of antimicrobial peptide PG-1. Further, all channels induce directional permeability of multiple ions across the bilayers from the lower to the upper leaflet. This similarity suggests that loosely-associated β-structure motifs can be a general feature of toxic, unregulated channels. In the absence of experimental high-resolution atomic structures of hIAPP channels in the membrane, this study represents a first attempt to delineate some of the main structural features of the hIAPP channels, for a better understanding of the origin of amyloid toxicity and the development of pharmaceutical agents.
authors.affiliation: Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, OH 44325, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.forename: Yin
authors.initials: Y
authors.lastname: Luo
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
authors.forename: Xiang
authors.initials: X
authors.lastname: Yu
authors.forename: Guanghong
authors.initials: G
authors.lastname: Wei
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007473:Ion Channels / Q000737:chemistry / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000378:metabolism*; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary
chemical_list: D000682:Amyloid; D023181:Antimicrobial Cationic Peptides; D007473:Ion Channels; D058228:Islet Amyloid Polypeptide; D008051:Lipid Bilayers