Structural dynamic investigation of Wnt signalling activation through Co-receptor LRP6

• Published in: Journal of biomolecular structure & dynamics 2025-01, p.1-14
• Main Authors: Dehghanbanadaki, N, Taghdir, M, Naderi-Manesh, H
• Format: Article
• Language: English
• ISSN: 0739-1102; 1538-0254; 1538-0254
• DOI: 10.1080/07391102.2024.2446667

Cancer sparks if the components of the cellular signaling network are aberrantly activated, leading to uncontrolled cell growth and proliferation. One of the most important players of this highly regulated network is the Wnt/β-catenin signaling, with a significant role in human health and disease. The critical co-receptor of this pathway, LRP6, is overexpressed in various cancer types and is a target for therapy. Therefore, understanding the details of the LRP6 structural activation mechanism is of tremendous importance. This research intended to compare the structural-dynamics features of the E3E4 functional domain of LRP6 induced by the activator Wnt3a and the inhibitor, Dkk1_C, compared with the receptor behavior in the apo-state. Using molecular docking, molecular dynamics simulation, and G_MMPBSA calculation, we characterized overlapping binding regions of Wnt3a and Dkk1_C on E3E4. Despite their overall similar interacting regions, Dkk1_C and Wnt induce remarkably different inter-blades hydrogen bonds, structural-dynamics behavior, and conformational energy landscape in E3E4. According to our findings, Dkk1_C stabilized the interaction. between BP3 blades 2-3, 3-4, and 4-5 and BP4 blades 1-6, 1-2, 2-3, and 3-4, aligned with apo-state. However, on the other hand, Wnt distinguishably destabilized the hydrogen bond networks of these blades. Our DCCM analysis also depicted a similar correlation pattern of apo and Dkk1-bound states, and dramatic differences in Wnt-bound state, with a specific enhancement of correlated movements in EGF4. These data provide atomistic-level clues of how natural regulators of Wnt signaling manipulate LRP6 dynamics and, therefore, guide the structure-based design of efficient artificial inhibitors/activators for the pathway.