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PDBsum entry 4c9r
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Ligase/signaling protein
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PDB id
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4c9r
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References listed in PDB file
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Key reference
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Title
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Structural and molecular basis of znrf3/rnf43 transmembrane ubiquitin ligase inhibition by the wnt agonist r-Spondin.
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Authors
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M.Zebisch,
Y.Xu,
C.Krastev,
B.T.Macdonald,
M.Chen,
R.J.Gilbert,
X.He,
E.Y.Jones.
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Ref.
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Nat Commun, 2013,
4,
2787.
[DOI no: ]
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PubMed id
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Abstract
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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
(ZNRF3ecto), a signalling-competent Furin1-Furin2 (Fu1-Fu2) fragment of Rspo2
(Rspo2Fu1-Fu2), and Rspo2Fu1-Fu2 in complex with ZNRF3ecto, or RNF43ecto. A
prominent loop in Fu1 clamps into equivalent grooves in the ZNRF3ecto and
RNF43ecto surface. Rspo binding enhances dimerization of ZNRF3ecto but not of
RNF43ecto. 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.
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