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Structural basis for transcriptional coactivator recognition by SMAD2 in TGF-β signaling

Ken-Ichi Miyazono1, Tomoko Ito1, Yui Fukatsu2

  • 1Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.

Science Signaling
|December 16, 2020
PubMed

Insights

Researchers uncovered the structural basis of how CBP interacts with SMAD2, a key component in transforming growth factor-beta (TGF-β) signaling. Disrupting this interaction may offer a new therapeutic strategy for TGF-β-related diseases.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Structural Biology

Background:

  • Transforming growth factor-beta (TGF-β) signaling regulates crucial cellular processes.
  • Dysregulation of TGF-β signaling is implicated in diseases like cancer and fibrosis.
  • SMAD proteins are key transcription factors mediating TGF-β signal transduction.

Purpose of the Study:

  • To elucidate the structural basis of the interaction between SMAD2 and the transcriptional coactivator CBP.
  • To understand how this interaction influences TGF-β-dependent gene expression.

Main Methods:

  • X-ray crystallography was used to determine the structure of the SMAD2 MH2 domain in complex with the CBP-binding region.
  • Cell-based assays were performed using mutated CBP peptides to assess the functional impact of the interaction.

Main Results:

  • Crystal structures revealed that CBP forms an amphiphilic helix that binds to the hydrophobic surface of the SMAD2 MH2 domain.
  • A mutated CBP peptide with enhanced SMAD2 binding repressed TGF-β-induced gene expression.
  • This suggests the interaction is critical for activating SMAD2-dependent gene expression.

Conclusions:

  • The study provides the structural foundation for understanding SMAD2-CBP complex formation.
  • Targeting the SMAD2-CBP interaction presents a potential therapeutic avenue for diseases driven by aberrant TGF-β signaling.

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