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

• Published in: Nature communications Vol. 14; no. 1; p. 3702
• Main Authors: Wang, Hongyang, Bienz, Mariann, Yan, Xiao-Xue, Xu, Wenqing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.06.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 101/1; 38/23; 38/70; 38/88; 38/91; 631/45/535/1266; 631/45/612; 631/80/86; 82/16; 82/29; 82/80; 82/83; 96/109; Adenomatous polyposis coli; Asparagine; B-cell lymphoma; beta Catenin - metabolism; Binding sites; Cancer; Crystal structure; DNA-binding protein; Drug development; Genes; Grooves; Humanities and Social Sciences; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; LIM-Homeodomain Proteins - metabolism; Lymphocytes B; Lymphoma; multidisciplinary; N-Terminus; Phenylalanine; Polyposis coli; Protein Domains; Proteins; Science; Science (multidisciplinary); Signaling; Single-stranded DNA; Single-stranded DNA-binding protein; Therapeutic applications; Therapeutic targets; Transcription Factors - genetics; Wnt protein; Wnt Signaling Pathway; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39439-9

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. The Wnt enhanceosome is responsible for the transactivation of Wnt target genes in response to stimulation of cells by extracellular Wnt signals. Here, Wang et al. show BCL9, Pygo, LDB1 and SSBP form a stable core complex within the Wnt enhanceosome. Furthermore, they determine the crystal structure of the Pygo2-LDB1-SSBP2 ternary complex, which provides a promising therapeutic target for blocking Wnt/β-catenin signaling in cancer.