8g4y
From Proteopedia
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Selective and precise activation of signaling transduction cascades is key for cellular reprogramming and tissue regeneration. However, the development of small- or large-molecule agonists for many signaling pathways has remained elusive and is rate limiting to realize the full clinical potential of regenerative medicine. Focusing on the Wnt pathway, here we describe a series of disulfide-constrained peptides (DCPs) that promote Wnt signaling activity by modulating the cell surface levels of ZNRF3, an E3 ubiquitin ligase that controls the abundance of the Wnt receptor complex FZD/LRP at the plasma membrane. Mechanistically, monomeric DCPs induce ZNRF3 ubiquitination, leading to its cell surface clearance, ultimately resulting in FZD stabilization. Furthermore, we engineered multimeric DCPs that induce expansive growth of human intestinal organoids, revealing a dependence between valency and ZNRF3 clearance. Our work highlights a strategy for the development of potent, biologically active Wnt signaling pathway agonists via targeting of ZNRF3. | Selective and precise activation of signaling transduction cascades is key for cellular reprogramming and tissue regeneration. However, the development of small- or large-molecule agonists for many signaling pathways has remained elusive and is rate limiting to realize the full clinical potential of regenerative medicine. Focusing on the Wnt pathway, here we describe a series of disulfide-constrained peptides (DCPs) that promote Wnt signaling activity by modulating the cell surface levels of ZNRF3, an E3 ubiquitin ligase that controls the abundance of the Wnt receptor complex FZD/LRP at the plasma membrane. Mechanistically, monomeric DCPs induce ZNRF3 ubiquitination, leading to its cell surface clearance, ultimately resulting in FZD stabilization. Furthermore, we engineered multimeric DCPs that induce expansive growth of human intestinal organoids, revealing a dependence between valency and ZNRF3 clearance. Our work highlights a strategy for the development of potent, biologically active Wnt signaling pathway agonists via targeting of ZNRF3. | ||
| - | Potent and selective binders of the E3 ubiquitin ligase ZNRF3 stimulate Wnt signaling and intestinal organoid growth.,Kschonsak YT, Gao X, Miller SE, Hwang S, Marei H, Wu P, Li Y, Ruiz K, Dorighi K, Holokai L, Perampalam P, Tsai WK, Kee YS, Agard NJ, Harris SF, Hannoush RN, de Sousa E Melo F Cell Chem Biol. | + | Potent and selective binders of the E3 ubiquitin ligase ZNRF3 stimulate Wnt signaling and intestinal organoid growth.,Kschonsak YT, Gao X, Miller SE, Hwang S, Marei H, Wu P, Li Y, Ruiz K, Dorighi K, Holokai L, Perampalam P, Tsai WK, Kee YS, Agard NJ, Harris SF, Hannoush RN, de Sousa E Melo F Cell Chem Biol. 2024 Jun 20;31(6):1176-1187.e10. doi: , 10.1016/j.chembiol.2023.11.006. Epub 2023 Dec 5. PMID:38056465<ref>PMID:38056465</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 8g4y" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 8g4y" style="background-color:#fffaf0;"></div> | ||
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| + | ==See Also== | ||
| + | *[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Structure of ZNRF3 ECD bound to peptide MK1-3.6.10
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