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Exploring DIX-DIX Homo- and Hetero-Oligomers in Wnt Signaling with AlphaFold2

Zehua Wen1, Lei Wang1, Shi-Wei Liu1

  • 1College of Chemical Engineering, Sichuan University of Science and Engineering, Zigong 64300, China.

Cells
|October 15, 2024
PubMed

Insights

Wnt signaling relies on DIX domain interactions. AlphaFold2 and PRODIGY predict binding affinities, revealing Axin2 and Dvl1 homodimers are stronger, and heterodimers generally exhibit higher affinity, clarifying Wnt pathway mechanisms.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Biochemistry

Background:

  • Wnt signaling is crucial for embryonic development and cancer.
  • DIX domain interactions within Axin, Dishevelled (Dvl), and Coiled-coil-DIX1 proteins are essential for Wnt/β-catenin pathway activation.
  • Specificities of DIX domain interactions remain unclear due to technical challenges.

Purpose of the Study:

  • To predict and analyze the structures and binding affinities of DIX domain homodimers and heterodimers.
  • To elucidate the specificity of DIX-mediated interactions in the Wnt signaling pathway.
  • To evaluate the utility of AlphaFold2 and PRODIGY in studying protein-protein interactions.

Main Methods:

  • Structure prediction of 6 homodimers and 22 heterodimers using AlphaFold2 (AF2) without templates.
  • Comparison of predicted structures with existing X-ray complex structures.
  • Calculation of binding affinities for DIX complexes using PRODIGY.

Main Results:

  • Axin2 DIX homodimer exhibits stronger binding affinity than Axin1 DIX homodimer.
  • Dvl1 DIX homodimer shows higher binding affinity compared to Dvl2 and Dvl3.
  • Coiled-coil-DIX1 (Ccd1) DIX homodimer has weaker binding than Axin1 DIX homodimer.
  • Generally, heterodimer interactions display stronger binding affinities than homodimers.

Conclusions:

  • Findings provide insights into the molecular mechanisms of Wnt signaling pathway activation.
  • Highlights the potential of AlphaFold2 and PRODIGY as powerful tools for investigating protein-protein interactions in signaling pathways.
  • Clarifies the differential binding affinities of various DIX domain interactions.
Keywords:
AlphaFold2DIXPRODIGYWnt signalingbinding affinity

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