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Article Abstract
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.
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