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

Autor: Wang H; School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Bienz M; Medical Research Council Laboratory of Molecular Biology, CB2 0QH, Cambridge, United Kingdom., Yan XX; National Laboratory of Biomacromolecules, Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. snow@ibp.ac.cn., Xu W; School of Life Science and Technology, ShanghaiTech University, Shanghai, China. xuwq2@shanghaitech.edu.cn.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Jun 22; Vol. 14 (1), pp. 3702. Date of Electronic Publication: 2023 Jun 22.
DOI: 10.1038/s41467-023-39439-9
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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