Misfolded amyloid ion channels present mobile beta-sheet subunits in contrast to conventional ion channels.

Biophysical Journal
Hyunbum JangRuth Nussinov

Abstract

In Alzheimer's disease, calcium permeability through cellular membranes appears to underlie neuronal cell death. It is increasingly accepted that calcium permeability involves toxic ion channels. We modeled Alzheimer's disease ion channels of different sizes (12-mer to 36-mer) in the lipid bilayer using molecular dynamics simulations. Our Abeta channels consist of the solid-state NMR-based U-shaped beta-strand-turn-beta-strand motif. In the simulations we obtain ion-permeable channels whose subunit morphologies and shapes are consistent with electron microscopy/atomic force microscopy. In agreement with imaged channels, the simulations indicate that beta-sheet channels break into loosely associated mobile beta-sheet subunits. The preferred channel sizes (16- to 24-mer) are compatible with electron microscopy/atomic force microscopy-derived dimensions. Mobile subunits were also observed for beta-sheet channels formed by cytolytic PG-1 beta-hairpins. The emerging picture from our large-scale simulations is that toxic ion channels formed by beta-sheets spontaneously break into loosely interacting dynamic units that associate and dissociate leading to toxic ionic flux. This sharply contrasts intact conventional gated ion channels t...Continue Reading

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Citations

Nov 16, 2011·Molecular Pharmaceutics·Bruce L KaganRuth Nussinov
Mar 24, 2010·Proceedings of the National Academy of Sciences of the United States of America·Hyunbum JangRatnesh Lal
Mar 2, 2013·Physical Chemistry Chemical Physics : PCCP·Hyunbum JangRuth Nussinov
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Oct 26, 2010·Journal of Molecular Biology·Hyunbum JangRuth Nussinov
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Jul 9, 2010·The Journal of Physical Chemistry. B·Hyunbum JangRuth Nussinov
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Mar 20, 2015·Chemical Reviews·Jessica Nasica-LabouzePhilippe Derreumaux

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