Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin

Matthias Zebisch, Yang Xu, Christos Krastev, Bryan T. MacDonald, Maorong Chen, Robert J. C. Gilbert, Xi He and E. Yvonne Jones ()
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Matthias Zebisch: Wellcome Trust Centre for Human Genetics, University of Oxford
Yang Xu: F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School
Christos Krastev: Wellcome Trust Centre for Human Genetics, University of Oxford
Bryan T. MacDonald: F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School
Maorong Chen: F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School
Robert J. C. Gilbert: Wellcome Trust Centre for Human Genetics, University of Oxford
Xi He: F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School
E. Yvonne Jones: Wellcome Trust Centre for Human Genetics, University of Oxford

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: Abstract The four R-spondin (Rspo) proteins are secreted agonists of Wnt signalling in vertebrates, functioning in embryogenesis and adult stem cell biology. Through ubiquitination and degradation of Wnt receptors, the transmembrane E3 ubiquitin ligase ZNRF3 and related RNF43 antagonize Wnt signalling. Rspo ligands have been reported to inhibit the ligase activity through direct interaction with ZNRF3 and RNF43. Here we report multiple crystal structures of the ZNRF3 ectodomain (ZNRF3ecto), a signalling-competent Furin1–Furin2 (Fu1–Fu2) fragment of Rspo2 (Rspo2Fu1–Fu2), and Rspo2Fu1–Fu2 in complex with ZNRF3ecto, or RNF43ecto. A prominent loop in Fu1 clamps into equivalent grooves in the ZNRF3ecto and RNF43ecto surface. Rspo binding enhances dimerization of ZNRF3ecto but not of RNF43ecto. Comparison of the four Rspo proteins, mutants and chimeras in biophysical and cellular assays shows that their signalling potency depends on their ability to recruit ZNRF3 or RNF43 via Fu1 into a complex with LGR receptors, which interact with Rspo via Fu2.

Date: 2013
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DOI: 10.1038/ncomms3787

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