Activation of Wnt Signaling Through co-receptor LRP6 : an structural dynamics characterization
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Najme Dehghanbanadaki,1 Majid Taghdir,2,* Hossein Naderi-Manesh ,3 Reza Hasan Sajedi,4
1. Tarbiat Modares University
2. Tarbiat Modares University
3. Tarbiat Modares University
4. Tarbiat Modares University
- Introduction: Wnt/β-catenin signaling is a highly evolutionary conserved pathway that emerges as the regulator of early embryonic development, stem cell biology and growth, and adult tissue homeostasis. One of the principal components of Wnt signaling is LRP6, a co-receptor comprised of two independent functional domains of E1E2 and E3E4 that is a promising target in Wnt-related cancers. In the normal cell state, the pathway is tightly regulated through extracellular ligand antagonists such as WIF-1 (Wnt-inhibitory factor 1), Cerberus, and Dickkopf (Dkk) family members.
Dkk1 competes to Wnt to bind to LRP6. Considering the significance of the Wnt signal transduction cascade in various aspects of human health and diseases, also the pivotal role of the co-receptor LRP6 in the pathway activation and inhibition, we decided to explore how ligand-binding changes the dynamic behavior of one of this co-receptor functional domain, E3E4.
- Methods: Here, using molecular docking and molecular dynamic simulation, we constructed the Wnt-E3E4 complex and observed the structural and dynamic characteristics of E3E4 upon binding to Dkk1, Wnt3a, and in the free state.
- Results: Based on our data supported by previous experimental research, compare to the free state, the E3E4 structural dynamic features are massively affected by ligand binding. Although the activator Wnt3a and the inhibitor Dkk1 have overlapping binding sites on E3E4, they induce exclusive patterns of structural flexibility, inter blades hydrogen bond-formation preference, and specific dynamic characteristics in E3E4 compare to the apo-state.
- Conclusion: Altogether, this work warrants structural dynamics insights on E3E4 and provides a useful approach in structural-based drug design against LRP6.
- Keywords: LRP6, Dkk1, Wnt3a, Molecular dynamics simulation
