期刊
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
卷 1818, 期 12, 页码 3121-3130出版社
ELSEVIER
DOI: 10.1016/j.bbamem.2012.08.012
关键词
hIAPP; Ion channel; Directional permeability; Molecular dynamic
资金
- Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]
- NIH, Frederick National Lab, Center for Cancer Research
- NSF [CBET-0952624, CBET-1158447]
- 3 M Non-Tenured Faculty Award
- National Natural Science Foundation of China [11074047]
- Research Fund for the Doctoral Program of Higher Education of China [RFDP-20100071110006]
- China Scholarship Council
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [1158447] Funding Source: National Science Foundation
- Div Of Chem, Bioeng, Env, & Transp Sys
- Directorate For Engineering [0952624] Funding Source: National Science Foundation
Interactions of human islet amyloid polypeptide (hIAPP or amylin) with the cell membrane are correlated with the dysfunction and death of pancreatic islet beta-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 beta-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 beta-strand-turn-beta-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 beta-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 beta, the beta(2)-microglobulin-derived K3 peptides, and the beta-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 beta-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. (C) 2012 Elsevier B.V. All rights reserved.
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