PDBsum entry 4ufr

Signaling protein

PDB id: 4ufr

Contents

Protein chains

459 a.a.

102 a.a.

Ligands

NAG ×2

Metals

_CL ×6

Waters ×150

PDB id:

4ufr

Name:

Signaling protein

Title:

Structure of the ectodomain of lgr5 in complex with r-spondin-2 (fu1fu2)

Structure:

Leucine-rich repeat-containing g-protein coupled receptor 5. Chain: a, c. Fragment: ectodomain, residues 32-487 and residues 538-544. Synonym: g-protein coupled receptor 49, g-protein coupled receptor 6 7, g-protein coupled receptor hg38, lgr5. Engineered: yes. Other_details: unstructured loop replaced with short linker, a488- h537 to ngnngd.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293t.

Resolution:

2.20Å R-factor: 0.209 R-free: 0.262

Authors:

M.Zebisch,E.Y.Jones

Key ref:

M.Zebisch and E.Y.Jones (2015). Crystal structure of R-spondin 2 in complex with the ectodomains of its receptors LGR5 and ZNRF3. J Struct Biol, 191, 149-155. PubMed id: 26123262 DOI: 10.1016/j.jsb.2015.05.008

Date:

18-Mar-15 Release date: 08-Jul-15

Protein chains

O75473  (LGR5_HUMAN) -  Leucine-rich repeat-containing G-protein coupled receptor 5 from Homo sapiens

Seq: 907 a.a.

Struc: 459 a.a.*

Protein chains

Q8BFU0  (RSPO2_MOUSE) -  R-spondin-2 from Mus musculus

Seq: 243 a.a.

Struc: 102 a.a.

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

DOI no: 10.1016/j.jsb.2015.05.008

J Struct Biol 191:149-155 (2015)

PubMed id: 26123262

Crystal structure of R-spondin 2 in complex with the ectodomains of its receptors LGR5 and ZNRF3.

M.Zebisch, E.Y.Jones.

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.