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Order from disorder for SMAD signaling
In response to ligands of the TGF-β superfamily, SMAD proteins regulate gene expression by cooperating with transcriptional coactivators such as CBP, which binds to the MH2 domains of SMAD2 and SMAD3. Miyazono et al. defined the region of CBP that was sufficient for binding to the SMAD2 MH2 domain and identified a point mutation in CBP that enhanced binding. Crystal structures showed that the SMAD2-binding region of CBP, which is predicted to be intrinsically disordered, adopted a helical conformation when bound to the three-helix bundle of the SMAD2 MH2 domain. Peptides corresponding to the SMAD2-interacting domain of CBP effectively competed with endogenous CBP and blocked ligand-induced, SMAD-dependent gene expression. Targeting the CBP-SMAD2 interface may therefore be an effective strategy for modulating TGF-β–dependent gene expression in pathological contexts.
Abstract
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.
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