TY - JOUR
T1 - Probing ion channel activity of human islet amyloid polypeptide (amylin)
AU - Zhao, Jun
AU - Luo, Yin
AU - Jang, Hyunbum
AU - Yu, Xiang
AU - Wei, Guanghong
AU - Nussinov, Ruth
AU - Zheng, Jie
N1 - Funding Information:
We thank Dr. Robert Tycko for providing the atomic coordinates of the hIAPP decamers. This project has been funded in whole or in part with federal funds from the M Non-Tenured Faculty Award. G.W. is thankful for the for financial support from the Frederick National Laboratory for Cancer Research, National Institutes of Health , under contract HHSN261200800001E . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US government. This research was supported [in part] by the Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research . J.Z. is thankful for the financial support from NSF grants (CAREER Award CBET-0952624 and CBET-1158447 ) and for 3 National Natural Science Foundation of China (Grant No. 11074047 ) and the Research Fund for the Doctoral Program of Higher Education of China ( RFDP-20100071110006 ). Y.L. is supported in part by the China Scholarship Council. This study in part utilized a 512-node Anton cluster at the National Resource for Biomedical Supercomputing (NRBSC) .
PY - 2012/12
Y1 - 2012/12
N2 - 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 β2-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.
AB - 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 β2-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.
KW - Directional permeability
KW - Ion channel
KW - Molecular dynamic
KW - hIAPP
UR - http://www.scopus.com/inward/record.url?scp=84865652060&partnerID=8YFLogxK
U2 - 10.1016/j.bbamem.2012.08.012
DO - 10.1016/j.bbamem.2012.08.012
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AN - SCOPUS:84865652060
SN - 0005-2736
VL - 1818
SP - 3121
EP - 3130
JO - Biochimica et Biophysica Acta - Biomembranes
JF - Biochimica et Biophysica Acta - Biomembranes
IS - 12
ER -