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PDBsum entry 4bsp
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Signaling protein
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PDB id
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4bsp
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References listed in PDB file
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Key reference
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Title
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Structure of stem cell growth factor r-Spondin 1 in complex with the ectodomain of its receptor lgr5.
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Authors
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W.C.Peng,
W.De lau,
F.Forneris,
J.C.Granneman,
M.Huch,
H.Clevers,
P.Gros.
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Ref.
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Cell Rep, 2013,
3,
1885-1892.
[DOI no: ]
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PubMed id
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Abstract
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Leucine-rich repeat-containing G protein-coupled receptors 4-6 (LGR4-LGR6) are
receptors for R-spondins, potent Wnt agonists that exert profound trophic
effects on Wnt-driven stem cells compartments. We present crystal structures of
a signaling-competent fragment of R-spondin 1 (Rspo1) at a resolution of 2.0 Å
and its complex with the LGR5 ectodomain at a resolution of 3.2 Å. Ecto-LGR5
binds Rspo1 at its concave leucine-rich-repeat (LRR) surface, forming a dimeric
2:2 complex. Fully conserved residues on LGR4-LGR6 explain promiscuous binding
of R-spondins. A phenylalanine clamp formed by Rspo1 Phe106 and Phe110 pinches
Ala190 of LGR5 and is critical for binding. Mutations related to congenital
anonychia reduce signaling, but not binding of Rspo1 to LGR5. Furthermore,
antibody binding to the extended loop of the C-terminal LRR cap of LGR5
activates signaling in a ligand-independent manner. Thus, our data reveal
binding of R-spondins to conserved sites on LGR4-LGR6 and, in analogy to FSHR
and related receptors, suggest a direct signaling role for LGR4-LGR6 in addition
to its formation of Wnt receptor and coreceptor complexes.
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