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PDBsum entry 2jtk

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protein links
Signaling protein PDB id
2jtk
Jmol
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    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9QYZ8  (DKK2_MOUSE) -  Dickkopf-related protein 2
Seq:
Struc:
259 a.a.
88 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 

 
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.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20015264 S.L.McDonald, and A.R.Silver (2011).
On target? Strategies and progress in the development of therapies for colorectal cancer targeted against WNT signalling.
  Colorectal Dis, 13, 360-369.  
21984209 Z.Cheng, T.Biechele, Z.Wei, S.Morrone, R.T.Moon, L.Wang, and W.Xu (2011).
Crystal structures of the extracellular domain of LRP6 and its complex with DKK1.
  Nat Struct Mol Biol, 18, 1204-1210.
PDB codes: 3s8v 3s8z 3s94
20101398 E.Piters, W.Balemans, T.L.Nielsen, M.Andersen, E.Boudin, K.Brixen, and W.Van Hul (2010).
Common genetic variation in the DKK1 gene is associated with hip axis length but not with bone mineral density and bone turnover markers in young adult men: results from the Odense Androgen Study.
  Calcif Tissue Int, 86, 271-281.  
  20111673 R.Shyam, X.Shen, B.Y.Yue, and K.K.Wentz-Hunter (2010).
Wnt gene expression in human trabecular meshwork cells.
  Mol Vis, 16, 122-129.  
20128690 S.Sue Ng, T.Mahmoudi, V.S.Li, P.Hatzis, P.J.Boersema, S.Mohammed, A.J.Heck, and H.Clevers (2010).
MAP3K1 functionally interacts with Axin1 in the canonical Wnt signalling pathway.
  Biol Chem, 391, 171-180.  
19477926 M.E.Binnerts, N.Tomasevic, J.M.Bright, J.Leung, V.E.Ahn, K.A.Kim, X.Zhan, S.Liu, S.Yonkovich, J.Williams, M.Zhou, D.Gros, M.Dixon, W.Korver, W.I.Weis, and A.Abo (2009).
The first propeller domain of LRP6 regulates sensitivity to DKK1.
  Mol Biol Cell, 20, 3552-3560.  
19333681 T.Kubota, T.Michigami, and K.Ozono (2009).
Wnt signaling in bone metabolism.
  J Bone Miner Metab, 27, 265-271.  
18502762 K.Wang, Y.Zhang, X.Li, L.Chen, H.Wang, J.Wu, J.Zheng, and D.Wu (2008).
Characterization of the Kremen-binding site on Dkk1 and elucidation of the role of Kremen in Dkk-mediated Wnt antagonism.
  J Biol Chem, 283, 23371-23375.  
18985752 S.G.Tevosian, and N.L.Manuylov (2008).
To beta or not to beta: canonical beta-catenin signaling pathway and ovarian development.
  Dev Dyn, 237, 3672-3680.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.