Structural basis for the transcriptional coactivator recognition mechanism by SMAD2 in TGF-β signaling
Ken-ichi Miyazono, Tomoko Ito, Yui Fukatsu, Hikaru Wada, Akira Kurisaki and Masaru Tanokura*
Transforming growth factor–β (TGF-β) proteins regulate multiple cellular functions, including cell proliferation, apoptosis, and extracellular matrix formation. The dysregulation of TGF-β signaling causes diseases such as cancer and fibrosis, and therefore, understanding the biochemical basis of TGF-β signal transduction is important for elucidating pathogenic mechanisms in these diseases. SMAD proteins are transcription factors that mediate TGF-β signaling–dependent gene expression. The transcriptional coactivator CBP directly interacts with the MH2 domains of SMAD2 to activate SMAD complex–dependent gene expression. Here, we report the structural basis for CBP recognition by SMAD2. The crystal structures of the SMAD2 MH2 domain in complex with the SMAD2-binding region of CBP showed that CBP forms an amphiphilic helix on the hydrophobic surface of SMAD2. The expression of a mutated CBP peptide that showed increased SMAD2 binding repressed SMAD2-dependent gene expression in response to TGF-β signaling in cultured cells. Disrupting the interaction between SMAD2 and CBP may therefore be a promising strategy for suppressing SMAD-dependent gene expression.
- : Science Signaling
- : 10.1126/scisignal.abb9043
- : https://stke.sciencemag.org/content/13/662/eabb9043.abstract