Research ArticleStructural Biology

Hydrophobic patches on SMAD2 and SMAD3 determine selective binding to cofactors

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Science Signaling  27 Mar 2018:
Vol. 11, Issue 523, eaao7227
DOI: 10.1126/scisignal.aao7227

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The SMAD cofactor code

SMADs are transcription factors that execute the transcriptional outputs of transforming growth factor–β (TGF-β) signaling. SMAD2 and SMAD3 form complexes with SMAD4 that translocate into the nucleus. Whether these complexes stimulate or repress the expression of target genes depends on cofactors that interact with the SMADs; therefore, the underlying mechanism is critical for the appropriate response to TGF-β signaling. Miyazono et al. determined the crystal structures of SMAD2 in complex with the transcriptional corepressor SKI and SMAD3 in complex with the transcription factor FOXH1. The authors identified multiple hydrophobic patches on the surfaces of SMAD2 and SMAD3 that mediated the interactions with these cofactors. The cofactors interacted with the SMADs through different subsets of these patches, suggesting that cooperation and competition between cofactors determine which cofactors bind to the SMADs in vivo.


The transforming growth factor–β (TGF-β) superfamily of cytokines regulates various biological processes, including cell proliferation, immune responses, autophagy, and senescence. Dysregulation of TGF-β signaling causes various diseases, such as cancer and fibrosis. SMAD2 and SMAD3 are core transcription factors involved in TGF-β signaling, and they form heterotrimeric complexes with SMAD4 (SMAD2-SMAD2-SMAD4, SMAD3-SMAD3-SMAD4, and SMAD2-SMAD3-SMAD4) in response to TGF-β signaling. These heterotrimeric complexes interact with cofactors to control the expression of TGF-β–dependent genes. SMAD2 and SMAD3 may promote or repress target genes depending on whether they form complexes with other transcription factors, coactivators, or corepressors; therefore, the selection of specific cofactors is critical for the appropriate activity of these transcription factors. To reveal the structural basis by which SMAD2 and SMAD3 select cofactors, we determined the crystal structures of SMAD3 in complex with the transcription factor FOXH1 and SMAD2 in complex with the transcriptional corepressor SKI. The structures of the complexes show that the MAD homology 2 (MH2) domains of SMAD2 and SMAD3 have multiple hydrophobic patches on their surfaces. The cofactors tether to various subsets of these patches to interact with SMAD2 and SMAD3 in a cooperative or competitive manner to control the output of TGF-β signaling.

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