May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Structural Basis of Selective Dkk Binding to LRP5/6 to Regulate Wnt Signaling
Author Affiliations & Notes
  • J. Zheng
    Structural Biology, St Jude Childrens Res Hosp, Memphis, Tennessee
  • Footnotes
    Commercial Relationships  J. Zheng, None.
  • Footnotes
    Support  ALSAC
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 2956. doi:https://doi.org/
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      J. Zheng; Structural Basis of Selective Dkk Binding to LRP5/6 to Regulate Wnt Signaling. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2956. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Dickkopf 2 (Dkk2) is an antagonist of the canonical Wnt signaling pathway andplays an essential role in the corneal fate of the ocular surface epithelium. Wnt antagonism of DKK2 requires the binding of the second cysteine-rich domain of Dkk2 to the Wnt co-receptor, LRP 5/6. However, the structural basis of the interaction between Dkk2 and LRP5/6 is unknown. In this study, we define the structure of the Dkk functional domain and elucidate its interactions with LRP5/6.

Methods: : Using NMR spectroscopy, we determined the solution structure of the functional domain of mouse Dkk2 (Dkk2C).

Results: : Then, guided by mutagenesis studies, we docked Dkk2C to the YWTD β-propeller domains of LRP5/6 and showed that the ligand binding site of the third LRP5/6 β-propeller domain matches Dkk2C best, suggesting that this domain binds to Dkk2C with the greatest affinity.

Conclusions: : Such differential binding affinity is likely to play an essential role in Dkk function in the canonical Wnt pathway.

Keywords: protein structure/function • signal transduction • protein purification and characterization 
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