Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin
Year: 2013
Type: article
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 (ZNRF3(ecto)), a signalling-competent Furin1-Furin2 (Fu1-Fu2) fragment of Rspo2 (Rspo2(Fu1-Fu2)), and Rspo2(Fu1-Fu2) in complex with ZNRF3(ecto), or RNF43(ecto). A prominent loop in Fu1 clamps into equivalent grooves in the ZNRF3(ecto) and RNF43(ecto) surface. Rspo binding enhances dimerization of ZNRF3(ecto) but not of RNF43(ecto). 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.
Source: Nature Communications
DOI: 10.1038/ncomms3787
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,979
Funders: Wellcome Trust, Diamond Light Source, Cancer Research UK, University of Oxford, National Institutes of Health, Intellectual and Developmental Disabilities Research Center, Medical Research Council, National Institute of General Medical Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1030164648, G117057553, G1241556041, G3797955763, G4525307788, G5215507216, G5846212695, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G7530496305, G8057470512, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G8975541179, G9000062381, G9000309734, G943165902
OpenAlex ID: W2167380532