PDBsum entry 1ijy

Signaling protein

PDB id: 1ijy

Contents

Protein chains

122 a.a. *

Waters ×279

* Residue conservation analysis

PDB id:

1ijy

Name:

Signaling protein

Title:

Crystal structure of the cysteine-rich domain of mouse frizzled 8 (mfz8)

Structure:

Frizzled homolog 8. Chain: a, b. Fragment: cysteine-rich domain. Engineered: yes. Mutation: yes

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Gene: fzd8. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell: ovary cells.

Biol. unit:

Tetramer (from PQS)

Resolution:

1.35Å R-factor: 0.225 R-free: 0.247

Authors:

C.E.Dann Iii,J.C.Hsieh,A.Rattner,D.Sharma,J.Nathans,D.J.Leahy

Key ref:

C.E.Dann et al. (2001). Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature, 412, 86-90. PubMed id: 11452312 DOI: 10.1038/35083601

Date:

01-May-01 Release date: 11-Jul-01

Protein chains

Q61091  (FZD8_MOUSE) -  Frizzled-8 from Mus musculus

Seq: 685 a.a.

Struc: 122 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1038/35083601

Nature 412:86-90 (2001)

PubMed id: 11452312

Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains.

C.E.Dann, J.C.Hsieh, A.Rattner, D.Sharma, J.Nathans, D.J.Leahy.

ABSTRACT

Members of the Frizzled family of seven-pass transmembrane proteins serve as receptors for Wnt signalling proteins. Wnt proteins have important roles in the differentiation and patterning of diverse tissues during animal development, and inappropriate activation of Wnt signalling pathways is a key feature of many cancers. An extracellular cysteine-rich domain (CRD) at the amino terminus of Frizzled proteins binds Wnt proteins, as do homologous domains in soluble proteins-termed secreted Frizzled-related proteins-that function as antagonists of Wnt signalling. Recently, an LDL-receptor-related protein has been shown to function as a co-receptor for Wnt proteins and to bind to a Frizzled CRD in a Wnt-dependent manner. To investigate the molecular nature of the Wnt signalling complex, we determined the crystal structures of the CRDs from mouse Frizzled 8 and secreted Frizzled-related protein 3. Here we show a previously unknown protein fold, and the design and interpretation of CRD mutations that identify a Wnt-binding site. CRDs exhibit a conserved dimer interface that may be a feature of Wnt signalling. This work provides a framework for studies of homologous CRDs in proteins including muscle-specific kinase and Smoothened, a component of the Hedgehog signalling pathway.

Selected figure(s)

Figure 1.
Figure 1: Crystal structure of the sFRP-3 and mFz8 CRDs. a, Ribbon diagram of the sFRP-3 CRD with elements of secondary structure numbered in order of appearance in the primary structure. b, Superposition of sFRP-3 CRD (blue) and mFz8 CRD (brown). c, Dimer of the sFRP-3 CRD observed in the crystal. d, Dimer of the mFz8 CRD observed in the crystal. a, c, d, -helices, blue; 3[10]-helices, yellow; -strands, green; coil, gold. Disulphide bonds are shown as ball-and-stick models in yellow and black. Images were generated by RIBBONS28.

Figure 4.
Figure 4: Surfaces involved in Wnt -CRD interactions modelled on the mFz8 CRD structure. Mutations that do not affect binding (green), that produce weak binding (orange) and that disrupt binding (red) are indicated. The orientation of the CRD surface on the left is identical to the ribbon diagrams in Fig. 1b; the orientation on the right is rotated 180° about a vertical axis. a, Locations of the 16 Gly-Ser-Gly (GSG) insertions in the DFz2 CRD that did not affect binding to XWnt8 -AP (green indicates the two amino acids that flank the point of insertion). b, Alanine scanning mutations in the mFz8 CRD. Alanine substitution of residues 117 and 118 (green) in the mFz8 CRD permitted binding when associated with two alanine substitutions upstream of this location, but not when associated with two alanine substitutions downstream. c, Homologue scanning mutations for mFz6/mFz8 CRD. Deletion of residues 114 -120 in the mFz8 CRD eliminates binding, but deletion of residues 114 -118 (green) does not. Images were generated by GRASP30.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2001, 412, 86-90) copyright 2001.

Figures were selected by the author.