Miyazono KI, Ito T, Fukatsu Y, Wada H, Kurisaki A, Tanokura M

Transforming growth factor-? (TGF-?) proteins regulate multiple cellular functions, including cell proliferation, apoptosis, and extracellular matrix formation. The dysregulation of TGF-? signaling causes diseases such as cancer and fibrosis, and therefore, understanding the biochemical basis of TGF-? signal transduction is important for elucidating pathogenic mechanisms in these diseases. SMAD proteins ...

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are transcription factors that mediate TGF-? 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-? signaling in cultured cells. Disrupting the interaction between SMAD2 and CBP may therefore be a promising strategy for suppressing SMAD-dependent gene expression.

Date: Dec. 15, 2019

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