Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation.

Autor: Qian Y; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Ma Z; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Xu Z; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Duan Y; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Xiong Y; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Xia R; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Zhu X; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Zhang Z; School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Tian X; School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Yin H; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Liu J; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Song J; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Lu Y; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Zhang A; School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Guo C; School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Jin L; Northeast Forestry University, Harbin, China., Kim WJ; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., Ke J; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China., Xu F; iHuman Institute, ShanghaiTech University, Shanghai, China., Huang Z; School of Life Science and Technology, Harbin Institute of Technology, Harbin, China., He Y; Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China. ajian.he@hit.edu.cn.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Sep 02; Vol. 15 (1), pp. 7644. Date of Electronic Publication: 2024 Sep 02.
DOI: 10.1038/s41467-024-52174-z
Abstrakt: WNT signaling is fundamental in development and homeostasis, but how the Frizzled receptors (FZDs) propagate signaling remains enigmatic. Here, we present the cryo-EM structure of FZD4 engaged with the DEP domain of Dishevelled 2 (DVL2), a key WNT transducer. We uncover a distinct binding mode where the DEP finger-loop inserts into the FZD4 cavity to form a hydrophobic interface. FZD4 intracellular loop 2 (ICL2) additionally anchors the complex through polar contacts. Mutagenesis validates the structural observations. The DEP interface is highly conserved in FZDs, indicating a universal mechanism by which FZDs engage with DVLs. We further reveal that DEP mimics G-protein/β-arrestin/GRK to recognize an active conformation of receptor, expanding current GPCR engagement models. Finally, we identify a distinct FZD4 dimerization interface. Our findings delineate the molecular determinants governing FZD/DVL assembly and propagation of WNT signaling, providing long-sought answers underlying WNT signal transduction.
(© 2024. The Author(s).)
Databáze: MEDLINE
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