Jang, Hyunbum; Arce, Fernando Teran; Ramachandran, Srinivasan; Capone, Ricardo; Lal, Ratnesh; Nussinov, Ruth
beta-Barrel Topology of Alzheimer's beta-Amyloid Ion Channels
JOURNAL OF MOLECULAR BIOLOGY, 404:917-934, DEC 17 2010

Emerging evidence supports the ion channel mechanism for Alzheimer's disease pathophysiology wherein small beta-amyloid (A beta) oligomers insert into the cell membrane, forming toxic ion channels and destabilizing the cellular ionic homeostasis Solid-state NMR-based data of amyloid oligomers in solution indicate that they consist of a double-layered beta-sheets where each monomer folds into beta-strand-turn-beta-strand and the monomers are stacked atop each other In the membrane, A beta peptides are proposed to be beta-type structures Experimental structural data available from atomic force microscopy (AFM) imaging of A beta oligomers in membranes reveal heterogeneous channel morphologies Previously, we modeled the channels in a non-tilted organization, parallel with the cross-membrane normal Here, we modeled a beta-barrel-like organization beta-Barrels are common in transmembrane toxin pores, typically consisting of a monomeric chain forming a pore, organized in a single-layered beta-sheet with antiparallel beta-strands and a right-handed twist Our explicit solvent molecular dynamics simulations of a range of channel sizes and polymorphic turns and comparisons of these with AFM image dimensions support a beta-barrel channel organization Different from the transmembrane beta-barrels where the monomers are folded into a circular beta-sheet with antiparallel beta-strands stabihzed by the connecting loops, these A beta barrels consist of multimeric chains forming double beta-sheets with parallel beta-strands, where the strands of each monomer are connected by a turn Although the A beta barrels adopt the right-handed beta-sheet twist, the barrels still break into heterogeneous, loosely attached subunits, in good agreement with AFM images and previous modeling The subunits appear mobile, allowing unregulated, hence toxic, ion flux (C) 2010 Elsevier Ltd All rights reserved

DOI:10.1016/j.jmb.2010.10.025

Find full text with Google Scholar.