Structural Basis of Frizzled-Wnt in Recognition of Aβ Unveils Mechanism of Aβ-Mediated Disruption

Although previous studies have confirmed that Aβ oligomers (AβO) can bind to Frizzled and inhibit Wnt signaling, the molecule details and the impact of AβO structural heterogeneity remain unclear. This study utilized molecular dynamics simulation, combined with free energy, RMSF and other calculations, to systematically explore the interaction molecule details of different histidine conformational forms (ε→δ) of AβO with the Fz-Wnt complex. The results indicated that AβO could induce significant conformational perturbations in both the dissociative Fz-CRD domain and the full Fz-Wnt complex. Notably, Aβ42 exhibited a stronger perturbing effect than Aβ40. Free energy calculations further revealed that the binding affinity of Aβ42 was significantly higher than that of Aβ40, with the FW-(εδδ)42 complex showing the strongest binding (ΔG* = -13.33 kcal/mol). At the residue level, hydrophobic residues (F4, L17, F19, M35, V40) serve as the core region driving AβO binding, whereas charged residues (D1, E3, R5, K16) modulate the interaction in different histidine tautomeric forms. Importantly, through analysis of how the "clasp" structure of Fz-Wnt was affected by AβO, the "unlocking" mechanism of AβO was revealed: The binding of AβO can cause a two-way size change of the clasp interface ranging from -0.35 nm (contraction) to +0.43 nm (expansion). In summary, this study for the first time reveals that histidine tautomerism regulates the binding affinity of Aβ-Fz and clarifies an allosteric "clamping-unlock" mechanism that goes beyond simple competitive inhibition, providing novel insights at the molecule level into AβO interfering with Wnt signal transduction.