Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers

Baburajendran, Nithya; Jauch, Ralf; Tan, Clara Yueh Zhen; Narasimhan, Kamesh; Kolatkar, Prasanna R.

doi:10.1093/nar/gkr500

Cited by 37 publications

(55 citation statements)

References 51 publications

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“…6B) is arranged on opposing faces of the DNA double helix, and direct protein-protein interactions between the DNA-binding domains are less likely in the present conformation, barring pronounced allosteric effects. It is possible that FOX-FOX binding cooperativity in this case is mediated by DNA conformational changes, as has been previously observed in multiple instances (Baburajendran et al 2011). …”

Section: Predicted Cooperative Interactions Are Rigid and Compactsupporting

confidence: 57%

Comprehensive prediction in 78 human cell lines reveals rigidity and compactness of transcription factor dimers

et al. 2013

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The binding of transcription factors (TFs) to their specific motifs in genomic regulatory regions is commonly studied in isolation. However, in order to elucidate the mechanisms of transcriptional regulation, it is essential to determine which TFs bind DNA cooperatively as dimers and to infer the precise nature of these interactions. So far, only a small number of such dimeric complexes are known. Here, we present an algorithm for predicting cell-type-specific TF-TF dimerization on DNA on a large scale, using DNase I hypersensitivity data from 78 human cell lines. We represented the universe of possible TF complexes by their corresponding motif complexes, and analyzed their occurrence at cell-type-specific DNase I hypersensitive sites. Based on~1.4 billion tests for motif complex enrichment, we predicted 603 highly significant celltype-specific TF dimers, the vast majority of which are novel. Our predictions included 76% (19/25) of the known dimeric complexes and showed significant overlap with an experimental database of protein-protein interactions. They were also independently supported by evolutionary conservation, as well as quantitative variation in DNase I digestion patterns. Notably, the known and predicted TF dimers were almost always highly compact and rigidly spaced, suggesting that TFs dimerize in close proximity to their partners, which results in strict constraints on the structure of the DNA-bound complex. Overall, our results indicate that chromatin openness profiles are highly predictive of cell-type-specific TF-TF interactions. Moreover, cooperative TF dimerization seems to be a widespread phenomenon, with multiple TF complexes predicted in most cell types.

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Section: Predicted Cooperative Interactions Are Rigid and Compactsupporting

confidence: 57%

Comprehensive prediction in 78 human cell lines reveals rigidity and compactness of transcription factor dimers

et al. 2013

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“…In all cases, an 11-residue b-hairpin was shown to be responsible for DNA sequence recognition, and is embedded in the major groove of DNA ( Fig. 1C -E) (Shi et al 1998;Baburajendran et al 2010Baburajendran et al , 2011. The amino acids responsible for specific contacts with the bases are conserved in all three MH1 domains ( Fig.…”

Section: Dna Binding Of Smad Complexes and Its Regulation By Posttranmentioning

confidence: 99%

Transcriptional Control by the SMADs

Hill

2016

Cold Spring Harb Perspect Biol

282

256

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The transforming growth factor-b (TGF-b) family of ligands elicit their biological effects by initiating new programs of gene expression. The best understood signal transducers for these ligands are the SMADs, which essentially act as transcription factors that are activated in the cytoplasm and then accumulate in the nucleus in response to ligand induction where they bind to enhancer/promoter sequences in the regulatory regions of target genes to either activate or repress transcription. This review focuses on the mechanisms whereby the SMADs achieve this and the functional implications. The SMAD complexes have weak affinity for DNA and limited specificity and, thus, they cooperate with other site-specific transcription factors that act either to actively recruit the SMAD complexes or to stabilize their DNA binding. In some situations, these cooperating transcription factors function to integrate the signals from TGF-b family ligands with environmental cues or with information about cell lineage. Activated SMAD complexes regulate transcription via remodeling of the chromatin template. Consistent with this, they recruit a variety of coactivators and corepressors to the chromatin, which either directly or indirectly modify histones and/or modulate chromatin structure.

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“…2,3 Crystal structure studies indicate that both Smad3 and Smad4 can directly bind to gene promoter elements to regulate target gene transcription. [4][5][6] Smad3 consists of MH1 and MH2 domains, which are connected by a linker region. The Smad3 C-terminus is phosphorylated by TβRI while the Smad3 linker can by phosphorylated by a number of kinases.…”

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confidence: 99%

The Smad3/Smad4/CDK9 complex promotes renal fibrosis in mice with unilateral ureteral obstruction

Jiang

Sun

et al. 2015

Kidney International

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Transforming growth factor-β1 (TGF-β1)/Smad signaling has a central role in the pathogenesis of renal fibrosis. Smad3 and Smad4 are pro-fibrotic, while Smad2 is anti-fibrotic. However, these Smads form heterogeneous complexes, the functions of which are poorly understood. Here we studied Smad complex function in renal fibrosis using the mouse model of unilateral ureteric obstruction. Mice heterozygous for Smad3/4 (Smad3/4) exhibited substantial protection from renal fibrosis through day 7 of obstruction, whereas Smad2/3 and Smad2/4 mice showed only modest protection. Formation of Smad3/Smad4/CDK9 complexes was an early event following obstruction in wild-type mice, which involved nuclear phosphorylation of the linker regions of Smad3. Significantly, Smad3 or Smad4 deficiency decreased the formation of Smad4/CDK9 or Smad3/CDK9 complex, Smad3 linker phosphorylation, and fibrosis but at different degrees. In vitro, TGF-β1 stimulation of collagen I promoter activity involved formation of Smad3/Smad4/CDK9 complexes, and overexpression of each component gave additive increases in collagen promoter activity. Co-administration of a CDK9 inhibitor and Smad3-specific inhibition achieved better protection from TGF-β1-induced fibrotic response in vitro and renal interstitial fibrosis in vivo. Thus formation of Smad3/Smad4/CDK9 complex drives renal fibrosis during ureteral obstruction. Formation of this complex represents a novel target for antifibrotic therapies.

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Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers

Cited by 37 publications

References 51 publications

Comprehensive prediction in 78 human cell lines reveals rigidity and compactness of transcription factor dimers

Comprehensive prediction in 78 human cell lines reveals rigidity and compactness of transcription factor dimers

Transcriptional Control by the SMADs

The Smad3/Smad4/CDK9 complex promotes renal fibrosis in mice with unilateral ureteral obstruction

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