title: Modeling the binding mechanism of Alzheimer's Aβ1-42 to nicotinic acetylcholine receptors based on similarity with snake α-neurotoxins.
abstract: 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.
authors.affiliation: Faculty of Medicine, Bar-Ilan University, Safed 14302, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Maatuk
authors.forename: Abraham O
authors.initials: AO
authors.lastname: Samson
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D030562:Databases, Protein; D062105:Molecular Docking Simulation; D009498:Neurotoxins / Q000737:chemistry / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D017386:Sequence Homology, Amino Acid; D012910:Snake Venoms / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D012910:Snake Venoms; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42)