PDBsum entry 2jtk

Signaling protein

PDB id: 2jtk

Contents

Protein chain

88 a.a. *

* Residue conservation analysis

PDB id:

2jtk

Name:

Signaling protein

Title:

A functional domain of a wnt signal protein

Structure:

Dickkopf-related protein 2. Chain: a. Fragment: dkk-type cys-2 region. Synonym: dkk-2, dickkopf-2, mdkk-2. Engineered: yes

Source:

Mus musculus. Mouse. Gene: dkk2. Expressed in: escherichia coli.

NMR struc:

20 models

Authors:

L.Chen,Y.Shao,J.Huang,J.Zheng

Key ref:

L.Chen et al. (2008). Structural insight into the mechanisms of wnt signaling antagonism by dkk. J Biol Chem, 283, 23364-23370. PubMed id: 18524778 DOI: 10.1074/jbc.M802375200

Date:

02-Aug-07 Release date: 08-Jul-08

Protein chain

Q9QYZ8  (DKK2_MOUSE) -  Dickkopf-related protein 2 from Mus musculus

Seq: 259 a.a.

Struc: 88 a.a.

DOI no: 10.1074/jbc.M802375200

J Biol Chem 283:23364-23370 (2008)

PubMed id: 18524778

Structural insight into the mechanisms of wnt signaling antagonism by dkk.

L.Chen, K.Wang, Y.Shao, J.Huang, X.Li, J.Shan, D.Wu, J.J.Zheng.

ABSTRACT

Dickkopf (Dkk) proteins are antagonists of the canonical Wnt signaling pathway and are crucial for embryonic cell fate and bone formation. Wnt antagonism of Dkk requires the binding of the C-terminal cysteine-rich domain of Dkk to the Wnt coreceptor, LRP5/6. However, the structural basis of the interaction between Dkk and low density lipoprotein receptor-related protein (LRP) 5/6 is unknown. In this study, we examined the structure of the Dkk functional domain and elucidated its interactions with LRP5/6. Using NMR spectroscopy, we determined the solution structure of the C-terminal cysteine-rich domain of mouse Dkk2 (Dkk2C). Then, guided by mutagenesis studies, we docked Dkk2C to the YWTD beta-propeller domains of LRP5/6 and showed that the ligand binding site of the third LRP5/6 beta-propeller domain matches Dkk2C best, suggesting that this domain binds to Dkk2C with higher affinity. Such differential binding affinity is likely to play an essential role in Dkk function in the canonical Wnt pathway.

Selected figure(s)

Figure 2.
FIGURE 2. Solution structure of Dkk2C. A, amino acid sequence alignment of C-terminal cysteine-rich domains of Dkks in mouse (m), human (h), Xenopus (x), rabbit (r), and zebrafish (z).β strand elements identified in the three-dimensional structure of Dkk2C are indicated at the top. Ten conserved cysteines are in bold type, and pairs of cysteines forming disulfide bridges are colored identically and linked by lines. Amino acids that contact the third β-propeller domain of LRP5 in the docked model are in bold and indicated by the red dots. B, stereo view of the peptide backbone (N, C- , C') determined by superimposition of 20 conformers of Dkk2C with the lowest target function values. The figure was generated by using MOLMOL (39). β strands are red; disulfide bridges are yellow. C, ribbon diagram of Dkk2C with the lowest target function values, generated by using MOLSCRIPT (40).

Figure 5.
FIGURE 5. Complex structure of the third β-propeller domain of LRP5 (LRP5-PD3) bound to Dkk2C. A, a ribbon diagram of the complex of LRP5-PD3 bound to Dkk2C. B, side chain interactions between Dkk2C and LRP5-PD3. Dashed lines represent hydrogen bonds. Residue numbers in brackets are the numbers in mouse Dkk1. Corresponding amino acids in LRP5-PD1 and LRP5-PD2 to those involved in LRP5-PD3 binding interface are listed in the right bottom panel. Figures were generated by using the Pymol program (DeLano Scientific).

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2008, 283, 23364-23370) copyright 2008.

Figures were selected by the author.