Sci. Signal., 2 July 2013
Structural Biology R-Spondin Co-Receptors
Annalisa M. VanHook
Science Signaling, AAAS, Washington, DC 20005, USA
R-spondins (RSPOs) are secreted growth factors that potentiate Wnt/β-catenin signaling by binding to leucine-rich repeat–containing G protein–coupled receptors (LGRs). RSPOs also bind to the transmembrane E3 ubiquitin ligases RNF43 and ZNRF3 and trigger their internalization. Because RNF43 and ZNRF3 promote the degradation of Wnt receptor complexes, the internalization of these E3 ligases potentiates Wnt signaling. Two studies report the structures of human RSPOs bound to the extracellular domains of LGRs and RNF43. Wang et al. solved the crystal structures of the extracellular domain (ECD) of LGR4, the N-terminal portion of RSPO1, and these proteins bound to one another; Chen et al. report the structure of an LGR5-RSPO1-RNF43 complex using the LGR5 ECD, the extracellular protease-associated domain of RNF43, and the N-terminal portion of RSPO1. Wang et al. found that the LGR4 ECD formed a horseshoe-shaped structure, the concave side of which contacted both of the furin-like cysteine-rich domains (CRDs) in the N-terminal portion of RSPO1. Using site-directed mutagenesis, the authors confirmed that the amino acids in RSPO1 that contacted LGR4 were critical for binding by providing both hydrophobic and hydrophilic interactions. These RSPO1-LGR4 interactions agreed with the RSPO1-LGR5 interactions in the structure of the LGR5-RSPO1-RNF43 complex solved by Chen et al. This study also revealed that a β-hairpin of RSPO1 inserted into a groove in RNF43 but that the crystallized extracellular domains of RNF43 and LGR5 did not contact one another. Binding of RSPO1 to LGR5 increased the affinity of RSPO1 for RNF43, suggesting that the interaction between RSPO1 and LGR5 stabilized the β-hairpin of RSPO1 to promote the RSPO1-RNF43 interaction. Residues corresponding to known disease-associated mutations in RSPO4 and RNF43 mapped to the RSPO-RNF43 interface. That the binding of RSPO1 to LGR5 promoted the interaction between RSPO1 and RNF43 is consistent with previous observations that, although RSPO1 can bind to ZNRF3 in the absence of LGR4, RSPO1-mediated membrane clearance of ZNRF3 depends on the presence of LGR4. These structural studies imply a model in which LGRs promote the binding of RSPOs to RNF43 or ZNRF3, ultimately leading to reduced degradation of Wnt receptor complexes and enhanced Wnt signaling.
Citation: A. M. VanHook, R-Spondin Co-Receptors. Sci. Signal. 6, ec151 (2013).
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