A Framework for Frizzled-G Protein Coupling and Implications to the PCP Signaling Pathways

Overview

Journal Cell Discov

Date 2024 Jan 5

PMID 38182578

Authors

Zhibin Zhang

Xi Lin

Ling Wei

Yiran Wu

Lu Xu

Lijie Wu

Xiaohu Wei

Suwen Zhao

Xiangjia Zhu

Fei Xu

Affiliations

Soon will be listed here.

Abstract

The ten Frizzled receptors (FZDs) are essential in Wnt signaling and play important roles in embryonic development and tumorigenesis. Among these, FZD6 is closely associated with lens development. Understanding FZD activation mechanism is key to unlock these emerging targets. Here we present the cryo-EM structures of FZD6 and FZD3 which are known to relay non-canonical planar cell polarity (PCP) signaling pathways as well as FZD1 in their G protein-coupled states and in the apo inactive states, respectively. Comparison of the three inactive/active pairs unveiled a shared activation framework among all ten FZDs. Mutagenesis along with imaging and functional analysis on the human lens epithelial tissues suggested potential crosstalk between the G-protein coupling of FZD6 and the PCP signaling pathways. Together, this study provides an integrated understanding of FZD structure and function, and lays the foundation for developing therapeutic modulators to activate or inhibit FZD signaling for a range of disorders including cancers and cataracts.

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