?-Barrel topology of Alzheimer's ?-amyloid ion channels.

ABSTRACT: Emerging evidence supports the ion channel mechanism for Alzheimer's disease pathophysiology wherein small ?-amyloid (A?) 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 ?-sheets where each monomer folds into ?-strand-turn-?-strand and the monomers are stacked atop each other. In the membrane, A? peptides are proposed to be ?-type structures. Experimental structural data available from atomic force microscopy (AFM) imaging of A? 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 ?-barrel-like organization. ?-Barrels are common in transmembrane toxin pores, typically consisting of a monomeric chain forming a pore, organized in a single-layered ?-sheet with antiparallel ?-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 ?-barrel channel organization. Different from the transmembrane ?-barrels where the monomers are folded into a circular ?-sheet with antiparallel ?-strands stabilized by the connecting loops, these A? barrels consist of multimeric chains forming double ?-sheets with parallel ?-strands, where the strands of each monomer are connected by a turn. Although the A? barrels adopt the right-handed ?-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.

SUBMITTER: Jang H 

PROVIDER: S-EPMC7291702 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature