Structural basis for inefficient G protein coupling by Frizzled receptors

Abstract

Frizzleds (FZDs) are class F G protein-coupled receptors (GPCRs) that primarily signal through Dishevelled (DVL) to initiate Wnt signalling, with evidence for context-specific coupling to heterotrimeric G proteins. Every FZD-G protein structure to date has been determined without an agonist, implying that agonist binding is not required for stable complex formation in vitro and directly contradicting the difficulty of demonstrating G protein coupling in cells. All these structures contain unassigned density between the receptor and the heterotrimeric G protein. From structures generated by single-particle cryo-electron microscopy (cryo-EM) of FZD7-Gs and FZD5-Gq, we identify this density as the detergent lauryl maltose neopentyl glycol (LMNG), which bridges the receptor and G protein to stabilise a weak, shallow interface. Absence of LMNG - in biochemical preparations and molecular dynamics simulations - destabilises the complex, showing that constitutive FZD-G protein engagement is intrinsically weak. The weak G protein coupling is governed by a conserved intracellular interface that when mutated differentially influences DVL and G protein signalling. Our findings show that LMNG has masked the instability of purified FZD-G protein complexes and provide the structural basis of FZDs as inherently weak G protein activators that are predisposed to DVL signalling.

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BibTeX RIS

BibTeX

@misc{burger2026structural,
  title = {{Structural basis for inefficient G protein coupling by Frizzled receptors}},
  author = {W. A. C. Burger and S. Das and H. Venugopal and A. S. Quinn and B. J. Williams-Noonan and L. L. L. Wong and T. T. Nguyen and J. R. Prendergast and N. S. Kirk and A. P. Leis and M. Dramicanin and T. Josephs and M. E. Call and G. Schulte and M. L. O'Mara and K. Huynh and A. Glukhova},
  howpublished = {bioRxiv},
  year = {2026},
  month = nov,
  doi = {10.64898/2026.11.03.763784},
  url = {https://www.biorxiv.org/content/10.64898/2026.11.03.763784v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Structural basis for inefficient G protein coupling by Frizzled receptors
AU  - W. A. C. Burger
AU  - S. Das
AU  - H. Venugopal
AU  - A. S. Quinn
AU  - B. J. Williams-Noonan
AU  - L. L. L. Wong
AU  - T. T. Nguyen
AU  - J. R. Prendergast
AU  - N. S. Kirk
AU  - A. P. Leis
AU  - M. Dramicanin
AU  - T. Josephs
AU  - M. E. Call
AU  - G. Schulte
AU  - M. L. O'Mara
AU  - K. Huynh
AU  - A. Glukhova
PY  - 2026
DA  - 2026/11/03
PB  - bioRxiv
DO  - 10.64898/2026.11.03.763784
UR  - https://www.biorxiv.org/content/10.64898/2026.11.03.763784v1
AB  - Frizzleds (FZDs) are class F G protein-coupled receptors (GPCRs) that primarily signal through Dishevelled (DVL) to initiate Wnt signalling, with evidence for context-specific coupling to heterotrimeric G proteins. Every FZD-G protein structure to date has been determined without an agonist, implying that agonist binding is not required for stable complex formation in vitro and directly contradicting the difficulty of demonstrating G protein coupling in cells. All these structures contain unassigned density between the receptor and the heterotrimeric G protein. From structures generated by single-particle cryo-electron microscopy (cryo-EM) of FZD7-Gs and FZD5-Gq, we identify this density as the detergent lauryl maltose neopentyl glycol (LMNG), which bridges the receptor and G protein to stabilise a weak, shallow interface. Absence of LMNG - in biochemical preparations and molecular dynamics simulations - destabilises the complex, showing that constitutive FZD-G protein engagement is intrinsically weak. The weak G protein coupling is governed by a conserved intracellular interface that when mutated differentially influences DVL and G protein signalling. Our findings show that LMNG has masked the instability of purified FZD-G protein complexes and provide the structural basis of FZDs as inherently weak G protein activators that are predisposed to DVL signalling.
ER  -

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