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Structural insights into Frizzled3 through nanobody modulators

Author

Listed:
  • James Hillier

    (University of Oxford)

  • Yuguang Zhao

    (University of Oxford)

  • Loic Carrique

    (University of Oxford)

  • Tomas Malinauskas

    (University of Oxford)

  • Reinis R. Ruza

    (University of Oxford)

  • Tao-Hsin Chang

    (University of Oxford)

  • Gangshun Yi

    (University of Oxford)

  • Helen M. E. Duyvesteyn

    (University of Oxford)

  • Jing Yu

    (University of Oxford)

  • Weixian Lu

    (University of Oxford)

  • Els Pardon

    (VUB
    VIB)

  • Jan Steyaert

    (VUB
    VIB)

  • Yanan Zhu

    (University of Oxford)

  • Tao Ni

    (University of Oxford)

  • E. Yvonne Jones

    (University of Oxford)

Abstract

The Wnt receptor Frizzled3 (FZD3) is important for brain axonal development and cancer progression. We report structures of FZD3 in complex with extracellular and intracellular binding nanobodies (Nb). The crystal structure of Nb8 in complex with the FZD3 cysteine-rich domain (CRD) reveals that the nanobody binds at the base of the lipid-binding groove and can compete with Wnt5a. Nb8 fused with the Dickkopf-1 C-terminal domain behaves as a FZD3-specific Wnt surrogate, activating β-catenin signalling. The cryo-EM structure of FZD3 in complex with Nb9 reveals partially resolved density for the CRD, which exhibits positional flexibility, and a transmembrane conformation that resembles active GPCRs. Nb9 binds to the cytoplasmic region of FZD3 at the putative Dishevelled (DVL) or G protein-binding site, competes with DVL binding, and inhibits GαS coupling. In combination, our FZD3 structures with nanobody modulators map extracellular and intracellular interaction surfaces of functional, and potentially therapeutic, relevance.

Suggested Citation

  • James Hillier & Yuguang Zhao & Loic Carrique & Tomas Malinauskas & Reinis R. Ruza & Tao-Hsin Chang & Gangshun Yi & Helen M. E. Duyvesteyn & Jing Yu & Weixian Lu & Els Pardon & Jan Steyaert & Yanan Zhu, 2024. "Structural insights into Frizzled3 through nanobody modulators," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51451-1
    DOI: 10.1038/s41467-024-51451-1
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    References listed on IDEAS

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    1. Shifan Yang & Yiran Wu & Ting-Hai Xu & Parker W. Waal & Yuanzheng He & Mengchen Pu & Yuxiang Chen & Zachary J. DeBruine & Bingjie Zhang & Saheem A. Zaidi & Petr Popov & Yu Guo & Gye Won Han & Yang Lu , 2018. "Crystal structure of the Frizzled 4 receptor in a ligand-free state," Nature, Nature, vol. 560(7720), pages 666-670, August.
    2. Claudia Y. Janda & Luke T. Dang & Changjiang You & Junlei Chang & Wim de Lau & Zhendong A. Zhong & Kelley S. Yan & Owen Marecic & Dirk Siepe & Xingnan Li & James D. Moody & Bart O. Williams & Hans Cle, 2017. "Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling," Nature, Nature, vol. 545(7653), pages 234-237, May.
    3. Shane C. Wright & Paweł Kozielewicz & Maria Kowalski-Jahn & Julian Petersen & Carl-Fredrik Bowin & Greg Slodkowicz & Maria Marti-Solano & David Rodríguez & Belma Hot & Najeah Okashah & Katerina Strako, 2019. "A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
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