Von der Struktur zur Funktion: Verstehen wie Wnt-Proteine an ihre Rezeptoren binden
Biophysik
Strukturbiologie
Zellbiologie
Zusammenfassung der Projektergebnisse
Wnt proteins are lipidated glycoproteins with essential functions in embryonic development and tissue homeostasis. Dysfunctions in Wnt-signaling can lead to various diseases, such as cancer and metabolic disorders. Wnt proteins can bind to multiple receptors, including ten FZDs and the receptor-tyrosine-kinases ROR1, ROR2, and RYK. Most are known for classical beta-catenin-dependent signaling, but Wnts and their receptors are involved other signaling pathways too. FZDs, for example, are not only crucial for beta-catenin-dependent signaling by recruiting the destruction complex via Dishevelled binding, but are also involved in G-protein recruitment similar to other G- protein-coupled receptors. Additionally, the functional relevance of Wnt-binding to certain RTKs is not well understood. This project aimed to gain a better understanding of Wnt-signaling by investigating Wnt-receptor interactions and receptor activation mechanisms. I showed that Wnt-acylation is not always necessary for receptor activation and binding. For this, I expressed functional Wnts carrying lipidation site mutations, which proved to be potent in activating beta-catenin-dependent signaling. Unfortunately, further effort to purify these Wnts for biochemical and biophysical analyses failed. Nevertheless, these Wnts have proven useful for investigations in cell signaling experiments. My inability to purify Wnts shifted my efforts towards the development of a expression strategy for full-length FZDs. These purified FZDs are currently being analyzed for lipid-binding characteristics and will be further employed for structural investigations and G-protein binding studies. Based on the previous finding in the lab, I also analyzed Wnt-binding to the RTKs ROR1 and ROR2, for which another manuscript is in preparation. Overall, though not every single goal was met (yet), I have made substantial progress with this fellowship in gaining more insights into how Wnts activate their receptors and what role Wnt-acylation plays in this. And with continued work using these unique reagents and approaches, I and confident that I will shed further light on the enigmatic contribution of Wnt-attached lipids to Wnt signaling.
Projektbezogene Publikationen (Auswahl)
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2018. Smoothening out the patches. Science 362, 26–27
Sommer, Anselm & Lemmon, Mark A.
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2019. Non-acylated Wnts Can Promote Signaling. Cell Reports 26, 875 883.e5
Speer, Kelsey F.; Sommer, Anselm; Tajer, Benjamin; Mullins, Mary C.; Klein, Peter S. & Lemmon, Mark A.
