Probing ion channel activity of human islet amyloid polypeptide (amylin)

Jun Zhao, Yin Luo, Hyunbum Jang, Xiang Yu, Guanghong Wei, Ruth Nussinov*, Jie Zheng

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


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.

Original languageEnglish
Pages (from-to)3121-3130
Number of pages10
JournalBiochimica et Biophysica Acta - Biomembranes
Issue number12
StatePublished - Dec 2012


FundersFunder number
National Science FoundationCBET-1158447, CBET-0952624
National Institutes of HealthHHSN261200800001E
National Cancer InstituteZ01BC010440
Directorate for Engineering0952624, 1158447
Frederick National Laboratory for Cancer Research
National Natural Science Foundation of China11074047
China Scholarship Council
Specialized Research Fund for the Doctoral Program of Higher Education of ChinaRFDP-20100071110006


    • Directional permeability
    • Ion channel
    • Molecular dynamic
    • hIAPP


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