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Structural basis of the interaction between BCL9-Pygo and LDB-SSBP complexes in assembling the Wnt enhanceosome

Author

Listed:
  • Hongyang Wang

    (ShanghaiTech University)

  • Mariann Bienz

    (Medical Research Council Laboratory of Molecular Biology)

  • Xiao-Xue Yan

    (Chinese Academy of Sciences)

  • Wenqing Xu

    (ShanghaiTech University)

Abstract

The Wnt enhanceosome is responsible for transactivation of Wnt-responsive genes and a promising therapeutic target for treatment of numerous cancers with Adenomatous Polyposis Coli (APC) or β-catenin mutations. How the Wnt enhanceosome is assembled remains poorly understood. Here we show that B-cell lymphoma 9 protein (BCL9), Pygopus (Pygo), LIM domain-binding protein 1 (LDB1) and single-stranded DNA-binding protein (SSBP) form a stable core complex within the Wnt enhanceosome. Their mutual interactions rely on a highly conserved N-terminal asparagine proline phenylalanine (NPF) motif of Pygo, through which the BCL9-Pygo complex binds to the LDB-SSBP core complex. Our crystal structure of a ternary complex comprising the N-terminus of human Pygo2, LDB1 and SSBP2 reveals a single LDB1-SSBP2 complex binding simultaneously to two Pygo2 molecules via their NPF motifs. These interactions critically depend on the NPF motifs which bind to a deep groove formed between LDB1 and SSBP2, potentially constituting a binding site for drugs blocking Wnt/β-catenin signaling. Analysis of human cell lines lacking LDB or Pygo supports the functional relevance of the Pygo-LDB1-SSBP2 interaction for Wnt/β-catenin-dependent transcription.

Suggested Citation

  • Hongyang Wang & Mariann Bienz & Xiao-Xue Yan & Wenqing Xu, 2023. "Structural basis of the interaction between BCL9-Pygo and LDB-SSBP complexes in assembling the Wnt enhanceosome," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39439-9
    DOI: 10.1038/s41467-023-39439-9
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    References listed on IDEAS

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    1. David M. Gay & Rachel A. Ridgway & Miryam Müller & Michael C. Hodder & Ann Hedley & William Clark & Joshua D. Leach & Rene Jackstadt & Colin Nixon & David J. Huels & Andrew D. Campbell & Thomas G. Bir, 2019. "Author Correction: Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer," Nature Communications, Nature, vol. 10(1), pages 1-1, December.
    2. Juliusz Mieszczanek & Laurens M. Tienen & Ashraf E. K. Ibrahim & Douglas J. Winton & Mariann Bienz, 2019. "Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    3. Tannishtha Reya & Hans Clevers, 2005. "Wnt signalling in stem cells and cancer," Nature, Nature, vol. 434(7035), pages 843-850, April.
    4. David M. Gay & Rachel A. Ridgway & Miryam Müller & Michael C. Hodder & Ann Hedley & William Clark & Joshua D. Leach & Rene Jackstadt & Colin Nixon & David J. Huels & Andrew D. Campbell & Thomas G. Bir, 2019. "Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
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