Structural insights into Frizzled3 through nanobody modulators

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, Tao Ni and E. Yvonne Jones ()
Additional contact information
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
Jan Steyaert: VUB
Yanan Zhu: University of Oxford
Tao Ni: University of Oxford
E. Yvonne Jones: University of Oxford

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51451-1

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