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 ?-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 ?-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 ?-strand-turn-?-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 ?-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 A?, the ?(2)-microglobulin-derived K3 peptides, and the ?-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 ?-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.

SUBMITTER: Zhao J 

PROVIDER: S-EPMC3455117 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature