Misfolded amyloid ion channels present mobile beta-sheet subunits in contrast to conventional ion channels.
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 that consist of tightly interacting alpha-helices that robustly prevent ion leakage, rather than hydrogen-bonded beta-strands. The simulations suggest why conventional gated channels evolved to consist of interacting alpha-helices rather than hydrogen-bonded beta-strands that tend to break in fluidic bilayers. Nature designs folded channels but not misfolded toxic channels.
Jang
Hyunbum
H
Center for Cancer Research Nanobiology Program, NCI-Frederick, SAIC-Frederick, Frederick, Maryland, USA. jangh2@mail.nih.gov
Arce
Fernando Teran
FT
Capone
Ricardo
R
Ramachandran
Srinivasan
S
Lal
Ratnesh
R
Nussinov
Ruth
R
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D020816:Amino Acid Motifs; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000378:metabolism; D016923:Cell Death; D002712:Chlorides / Q000378:metabolism; D007473:Ion Channels / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D017136:Ion Transport; D008958:Models, Molecular; D008970:Molecular Weight; D010539:Permeability; D017510:Protein Folding; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity
D000682:Amyloid; D023181:Antimicrobial Cationic Peptides; D002712:Chlorides; D007473:Ion Channels; D021122:Protein Subunits; C094880:protegrin-1