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Elucidating the Role of Hydroxylated Phenylalanine in the Formation and Structure of Cross-Linked Aβ Oligomers

Zhang, Shuting, Fox, Dillion M., Urbanc, Brigita
TheJournal of physical chemistry 2019 v.123 no.5 pp. 1068-1084
Alzheimer disease, amyloid, chemical bonding, copper, crosslinking, histidine, hydrogen peroxide, hydroxylation, lysine, neurotoxicity, phenylalanine, solvents, tyrosine
Amyloid β-protein (Aβ) oligomers play a seminal role in Alzheimer’s disease (AD). Cross-linking (X-linking), which can be used to determine Aβ oligomer size distributions experimentally, was reported to stabilize Aβ oligomers. Aβ oligomers X-linked in the presence of copper and hydrogen peroxide may represent the proximate neurotoxic species in AD. Our previous computational study demonstrated that X-linking of Aβ₄₀ and Aβ₄₂ oligomers via tyrosines alone cannot explain experimental findings. Here, we explore three plausible X-linking mechanisms, which involve, in addition to tyrosine, also lysine (mechanism 1), histidine (mechanism 2), and hydroxylated phenylalanine (mechanism 3). By examining the effect of X-linking on oligomer size distributions, we show that only mechanism 3 is consistent with experimental data. Our findings provide important insights into the two-step X-linking via mechanism 3, which consists of a simple covalent bonding via tyrosines in the presence of hydroxylated phenylalanines, followed by covalent bonding among tyrosines and hydroxylated phenylalanines. Structural analysis of X-linked Aβ oligomers revealed increased solvent exposure at the N-terminal region, which was previously associated with increased oligomer toxicity. Our results elucidate a potentially important role of phenylalanine hydroxylation and increased toxicity of Aβ oligomers induced by X-linking.