IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-51451-1.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-51451-1
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-51451-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Julien Bous & Julia Kinsolving & Lukas Grätz & Magdalena M. Scharf & Jan Hendrik Voss & Berkay Selcuk & Ogün Adebali & Gunnar Schulte, 2024. "Structural basis of frizzled 7 activation and allosteric regulation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Yu Qian & Zhengxiong Ma & Zhenmei Xu & Yaning Duan & Yangjie Xiong & Ruixue Xia & Xinyan Zhu & Zongwei Zhang & Xinyu Tian & Han Yin & Jian Liu & Jing Song & Yang Lu & Anqi Zhang & Changyou Guo & Lihua, 2024. "Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Lukas Grätz & Maria Kowalski-Jahn & Magdalena M. Scharf & Pawel Kozielewicz & Michael Jahn & Julien Bous & Nevin A. Lambert & David E. Gloriam & Gunnar Schulte, 2023. "Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Ohman Kwon & Hana Lee & Jaeeun Jung & Ye Seul Son & Sojeong Jeon & Won Dong Yoo & Naeun Son & Kwang Bo Jung & Eunho Choi & In-Chul Lee & Hyung-Jun Kwon & Chuna Kim & Mi-Ok Lee & Hyun-Soo Cho & Dae Soo, 2024. "Chemically-defined and scalable culture system for intestinal stem cells derived from human intestinal organoids," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Jie Ding & Sung-Jin Lee & Lukas Vlahos & Kanako Yuki & Cara C. Rada & Vincent Unen & Meghah Vuppalapaty & Hui Chen & Asmiti Sura & Aaron K. McCormick & Madeline Tomaske & Samira Alwahabi & Huy Nguyen , 2023. "Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD4-selective WNT surrogate in mice," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51451-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.