ArticleJournal of structural biology2015
Crystal structure of R-spondin 2 in complex with the ectodomains of its receptors LGR5 and ZNRF3.
Article in Journal of structural biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 48 citations in OpenAlex.
- LGR5: from stem cell marker to therapeutic target.Trends in cancer · 2026Review
- Anti-tumor activity of camptothecin analog conjugate of an RSPO4-based peptibody targeting LGR4/5/6 in preclinical models of colorectal cancer.British journal of cancer · 2025Article
- Structural insights into Wnt/β-catenin signaling regulation by LGR4, R-spondin, and ZNRF3.Nature communications · 2025Article
- Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling.Nature communications · 2025Article
- Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances.Signal transduction and targeted therapy · 2025Review
- Structural insights into the LGR4-RSPO2-ZNRF3 complexes regulating WNT/β-catenin signaling.Nature communications · 2025Article
- LGR4 and LGR5 form distinct homodimers that only LGR4 complexes with RNF43/ZNRF3 to provide high affinity binding of R-spondin ligands.Scientific reports · 2023Article
- Receptor control by membrane-tethered ubiquitin ligases in development and tissue homeostasis.Current topics in developmental biology · 2022Article
- Review: The evolution of peptidergic signaling in Cnidaria and Placozoa, including a comparison with Bilateria.Frontiers in endocrinology · 2022Review
- Drug Conjugates of Antagonistic R-Spondin 4 Mutant for Simultaneous Targeting of Leucine-Rich Repeat-Containing G Protein-Coupled Receptors 4/5/6 for Cancer Treatment.Journal of medicinal chemistry · 2021Article
- Rspo2 inhibits TCF3 phosphorylation to antagonize Wnt signaling during vertebrate anteroposterior axis specification.Scientific reports · 2021Article
- USP42 protects ZNRF3/RNF43 from R-spondin-dependent clearance and inhibits Wnt signalling.EMBO reports · 2021Article
- Controlling Wnt Signaling Specificity and Implications for Targeting WNTs Pharmacologically.Handbook of experimental pharmacology · 2021Article
- Unlike LGR4, LGR5 potentiates Wnt-β-catenin signaling without sequestering E3 ligases.Science signaling · 2020Article
- RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer.The EMBO journal · 2020Article
- The structural biology of canonical Wnt signalling.Biochemical Society transactions · 2020Review
- Article
- Canonical WNT/β-Catenin Signaling Activated by WNT9b and RSPO2 Cooperation Regulates Facial Morphogenesis in Mice.Frontiers in cell and developmental biology · 2020Article
- Article
- Tales from the crypt: intestinal niche signals in tissue renewal, plasticity and cancer.Open biology · 2018Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The four secreted R-spondin (Rspo1-4) proteins of vertebrates function as stem cell growth factors and potentiate canonical Wnt signalling. Rspo proteins act by cross-linking members of two cell surface receptor families, complexing the stem cell markers LGR4-6 with the Frizzled-specific E3 ubiquitin ligases ZNRF3/RNF43. The consequent internalisation of the ternary LGR-Rspo-E3 complex removes the E3 ligase activity, which otherwise targets the Wnt receptor Frizzled for degradation, and thus enhances Wnt signalling. Multiple combinations of LGR4-6, Rspo1-4 and ZNRF3/RNF43 are possible, implying the existence of generic interaction determinants, but also of specific differences in complex architecture and activity. We present here a high resolution crystal structure of an ectodomain variant of human LGR5 (hLGR5ecto) complexed with a signalling competent fragment of mouse Rspo2 (mRspo2Fu1-Fu2). The structure shows that the particularly potent Rspo2 ligand engages LGR5 in a fashion almost identical to that reported for hRSPO1. Comparison of our hLGR5ecto structure with previously published structures highlights a surprising plasticity of the LGR ectodomains, characterised by a nearly 9° or larger rotation of the N-terminal half of the horseshoe-like fold relative to the C-terminal half. We also report a low resolution hLGR5-mRspo2Fu1-Fu2-mZNRF3ecto ternary complex structure. This crystal structure confirms our previously suggested hypothesis, showing that Rspo proteins cross-link LGRs and ZNRF3 into a 2:2:2 complex, whereas a 1:1:1 complex is formed with RNF43.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.