2025/05/21 by Heng Zhou, Zheyu Xu, Yue Xiong +7 · 1 voice
Biochemistry, Genetics and Molecular Biology · #Cancer-related gene regulation #TGF-β signaling in diseases #Ubiquitin and proteasome pathways
paper · pdf · doi:10.1002/1873-3468.70073
openalex created_date 2025/05/21 · openalex publication_date 2025/05/21 · openalex updated_date 2026/08/01
Homeobox protein TGIF1 plays crucial roles in human development and body functions, partly by functioning as a corepressor in TGFβ signaling pathway. TGIF1 interacts with the MH2 domain of SMAD2 and is subsequently recruited to SMAD-binding elements to repress TGFβ-responsive gene expression. Here, through NMR titration, HDX-MS, and AlphaFold3 modeling, we reveal that a vertebrate-conserved short motif (I302-L310) of TGIF1 binds to a groove on the surface of SMAD2-MH2. The TGIF1-binding sites of SMAD2 overlap with those for its coactivators. BiFC assays verified that α2-β8 loop of SMAD2-MH2 plays a key role in binding to TGIF1. This study provides structural insight into the mechanism by which TGIF1 acts as a corepressor of SMAD2, probably through competing with coactivators for binding.