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Wnt antagonists bind through a short peptide to the first β-propeller domain of LRP5/6

Eric Bourhis1, Weiru Wang, Christine Tam

  • 1Department of Early Discovery Biochemistry, Genentech Research and Early Development, 1 DNA Way, South San Francisco, CA 94080, USA.

Structure (London, England : 1993)
|September 28, 2011
PubMed

Insights

Wnt pathway inhibitors like DKK1 and sclerostin (SOST) bind to LRP5/6 coreceptors. A newly discovered tripeptide motif on these inhibitors is crucial for binding and Wnt signaling inhibition, explaining bone density mutations.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Bone Biology

Background:

  • Wnt pathway inhibitors, DKK1 and sclerostin (SOST), are key therapeutic targets for bone diseases.
  • Wnt coreceptors LRP5/6 are critical, with mutations affecting bone mineral density (BMD).

Purpose of the Study:

  • To elucidate the structural basis of Wnt inhibitor binding to LRP5/6.
  • To understand the role of the LRP5/6 E1 domain in Wnt signaling modulation.

Main Methods:

  • X-ray crystallography of LRP6 E1 domain bound to an antibody.
  • Sequence analysis to identify conserved motifs in Wnt inhibitors.
  • Functional assays to assess inhibitor binding and Wnt pathway activity.

Main Results:

  • The LRP6 E1 domain functions as a peptide recognition module.
  • A conserved tripeptide motif in DKK1 and SOST matches the LRP6 E1 binding sequence.
  • This motif is essential for DKK1 and SOST binding to LRP6 and their inhibitory function.

Conclusions:

  • The identified tripeptide motif provides a structural mechanism for Wnt inhibitor action.
  • This finding explains the impact of bone overgrowth (BMD) mutations on LRP5/6.
  • Offers insights for developing targeted therapies for bone disorders.

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