4UFS

Low resolution structure R-spondin-2 (Fu1Fu2) in complex with the ectodomains of LGR5 and ZNRF3

Summary for 4UFS

• Entry DOI: 10.2210/pdb4ufs/pdb
• Related: 4UFR
• Descriptor: LEUCINE-RICH REPEAT-CONTAINING G-PROTEIN COUPLED RECEPTOR 5, R-SPONDIN-2, E3 UBIQUITIN-PROTEIN LIGASE ZNRF3 (3 entities in total)
• Functional Keywords: signaling protein, wnt, lgr, rspo
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cell membrane; Multi-pass membrane protein: O75473; Secreted : Q8BFU0; Cell membrane ; Single-pass type I membrane protein : Q5SSZ7
• Total number of polymer chains: 3
• Total formula weight: 86258.88

Authors

Zebisch, M.,Jones, E.Y. (deposition date: 2015-03-18, release date: 2015-07-08, Last modification date: 2024-11-20)

Primary citation

Zebisch, M.,Yvonne Jones, E.
Crystal Structure of R-Spondin 2 in Complex with the Ectodomains of its Receptors Lgr5 and Znrf3.
J.Struct.Biol., 191:149-, 2015

PubMed 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.

PubMed: 26123262
DOI: 10.1016/J.JSB.2015.05.008

Experimental method

X-RAY DIFFRACTION (4.8 Å)