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TitleA framework for Frizzled-G protein coupling and implications to the PCP signaling pathways.
Journal, issue, pagesCell Discov, Vol. 10, Issue 1, Page 3, Year 2024
Publish dateJan 5, 2024
AuthorsZhibin Zhang / Xi Lin / Ling Wei / Yiran Wu / Lu Xu / Lijie Wu / Xiaohu Wei / Suwen Zhao / Xiangjia Zhu / Fei Xu /
PubMed AbstractThe 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. ...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.
External linksCell Discov / PubMed:38182578 / PubMed Central
MethodsEM (single particle)
Resolution3.2 - 3.5 Å
Structure data

36111

8j9n

EMDB-36111, PDB-8j9n:
Gq bound FZD1 in ligand-free state
Method: EM (single particle) / Resolution: 3.5 Å

36112

8j9o

EMDB-36112, PDB-8j9o:
Cryo-EM structure of inactive FZD1
Method: EM (single particle) / Resolution: 3.4 Å

36258

8jh7

EMDB-36258, PDB-8jh7:
FZD6 in inactive state
Method: EM (single particle) / Resolution: 3.2 Å

36261

8jhb

EMDB-36261, PDB-8jhb:
FZD6 Gs complex
Method: EM (single particle) / Resolution: 3.3 Å

36262

8jhc

EMDB-36262, PDB-8jhc:
FZD3 in inactive state
Method: EM (single particle) / Resolution: 3.3 Å

36266

8jhi

EMDB-36266, PDB-8jhi:
FZD3-Gs complex
Method: EM (single particle) / Resolution: 3.2 Å

Source
  • homo sapiens (human)
  • vicugna pacos (alpaca)
  • mus (mice)
  • synthetic construct (others)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / FZD1-Gq / class-F / Frizzled receptor / Complex / Frizzled / FZD1 / FZD6 / Complex. / FZD3

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