Structural convergence among diverse, toxic beta-sheet ion channels.
Recent studies show that an array of beta-sheet peptides, including N-terminally truncated Abeta peptides (Abeta(11-42/17-42)), K3 (a beta(2)-microglobulin fragment), and protegrin-1 (PG-1) peptides form ion channel-like structures and elicit single channel ion conductance when reconstituted in lipid bilayers and induce cell damage through cell calcium overload. Striking similarities are observed in the dimensions of these toxic channels irrespective of their amino acid sequences. However, the intriguing question of preferred channel sizes is still unresolved. Here, exploiting ssNMR-based, U-shaped, beta-strand-turn-beta-strand coordinates, we modeled truncated Abeta peptide (p3) channels with different sizes (12- to 36-mer). Molecular dynamics (MD) simulations show that optimal channel sizes of the ion channels presenting toxic ionic flux range between 16- and 24-mer. This observation is in good agreement with channel dimensions imaged by AFM for Abeta(9-42), K3 fragment, and PG-1 channels and highlights the bilayer-supported preferred toxic beta-channel sizes and organization, regardless of the peptide sequence.
Jang
Hyunbum
H
Center for Cancer Research Nanobiology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA.
Teran Arce
Fernando
F
Ramachandran
Srinivasan
S
Capone
Ricardo
R
Lal
Ratnesh
R
Nussinov
Ruth
R
D016229:Amyloid beta-Peptides / Q000737:chemistry; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry; D007473:Ion Channels / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry; D018625:Microscopy, Atomic Force; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry; D017433:Protein Structure, Secondary
D016229:Amyloid beta-Peptides; D023181:Antimicrobial Cationic Peptides; D007473:Ion Channels; D008051:Lipid Bilayers; D010455:Peptides; C094880:protegrin-1