Amyloid‑β “Co-assembles” with Coatomer Subunit Delta (δ-COP)

Previous studies showed that δ-COP interacts with APP and regulates its intracellular trafficking, while an important reduction in the level of Aβ plaques was observed in AD/δ-COP I422T mice. Here, we show that δ-COP interacts directly with Aβ assemblies according to experiments and simulations. Experiments suggest a two-binding site model, one with high affinity and one with lower affinity. Simulations comply with experiments and provide mechanistic biophysical insights into the high-affinity interactions, comprising a “co-assembly-like” β-sheet interaction within nearly identical domains 426DGEYRHDS433 of δ-COP and 1DAEFRHDS8 of Aβ, complemented by interactions between 416GVGAPVIGEI425 of δ-COP and 13HHQKLVFFAED23 of Aβ, with a β-bridge between δ-COP I422 and Aβ D23. As such, our simulations highlight the role of I422, which is also investigated in comparison to T422. Our studies can provide impetus for the future investigation of the interaction between δ-COP and Aβ, particularly in its involvement in intracellular trafficking in Alzheimer’s disease.