Modeling the binding mechanism of Alzheimer's Aβ1–42 to nicotinic acetylcholine receptors based on similarity with snake α-neurotoxins
Copyright policy )Modeling the binding mechanism of Alzheimer's Aβ1–42 to nicotinic acetylcholine receptors based on similarity with snake α-neurotoxins
For over a decade, it has been known that amyloid β (Aβ) peptides of Alzheimer's disease bind to the nicotinic α7 acetylcholine receptor (AChR) with picomolar affinity, and that snake α-neurotoxins competitively inhibit this binding. Here we propose a model of the binding mechanism of Aβ peptides to α7-AChR at atomic level. The binding mechanism is based on sequence and structure similarities of Aβ residues with functional residues of snake α-neurotoxins (ATX) in complex with AChR. The binding mechanism involves residue (Aβ)K28 (similar to (ATX)R32) which forms cation/π interactions in the acetylcholine binding site, and residues (Aβ)G29-(Aβ)I32 [GAII] (similar to (ATX)G33-(ATX)I36 [GTII]) which form an intermolecular β-sheet with residues (α7)F189-(α7)E191 of AChR. Through these interactions, we propose that the AChR serves as a chaperone for Aβ conformational changes from α- to β-hairpin. The interactions which block channel opening provide fundamental insight into Aβ neurotoxicity and cognition impairment, that could contribute to pathogenic processes in Alzheimer's disease, thus paving the way for structure based therapies.
- Bar-Ilan University Israel
Protein Folding, Amyloid beta-Peptides, Binding Sites, Sequence Homology, Amino Acid, Protein Conformation, Neurotoxins, Receptors, Nicotinic, Peptide Fragments, Molecular Docking Simulation, Structure-Activity Relationship, Alzheimer Disease, Sequence Analysis, Protein, Protein Interaction Mapping, Animals, Protein Interaction Domains and Motifs, Amino Acid Sequence, Databases, Protein, Sequence Alignment, Protein Binding, Snake Venoms
Protein Folding, Amyloid beta-Peptides, Binding Sites, Sequence Homology, Amino Acid, Protein Conformation, Neurotoxins, Receptors, Nicotinic, Peptide Fragments, Molecular Docking Simulation, Structure-Activity Relationship, Alzheimer Disease, Sequence Analysis, Protein, Protein Interaction Mapping, Animals, Protein Interaction Domains and Motifs, Amino Acid Sequence, Databases, Protein, Sequence Alignment, Protein Binding, Snake Venoms
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