Features of a Smad3 MH1-DNA Complex

By J. Chai, Jia-Wei Wu, Nieng Yan, J. Massagué, N. Pavletich, Yigong Shi. 2003

85 citations recorded by the source corpus.

The Smad family of proteins mediates transforming growth factor-β signaling from cell membrane to the nucleus. In the nucleus, Smads serve as transcription factors by directly binding to specific DNA sequences and regulating the expression of ligand-response genes. A previous structural analysis, at 2.8-Å resolution, revealed a novel DNA-binding mode for the Smad MH1 domain but did not allow accurate assignment of the fines features of protein-DNA interactions. The crystal structure of a Smad3 MH1 domain bound to a palindromic DNA sequence, determined at 2.4-Å resolution, reveals a surprisingly important role for water molecules. The asymmetric placement of the DNA-binding motif (a conserved 11-residue β-hairpin) in the major groove of DNA is buttressed by seven well ordered water molecules. These water molecules make specific hydrogen bonds to the DNA bases, the DNA phosphate backbones, and several critical Smad3 residues. In addition, the MH1 domain is found to contain a bound zinc atom using four invariant residues among Smad proteins, three cysteines and one histidine. Removal of the zinc atom results in compromised DNA binding activity. These results define the Smad MH1 domain as a zinc-coordinating module that exhibits unique DNA binding properties.

Subfields: Cell Biology, Molecular Biology

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Citations in the corpus

ECOD: An Evolutionary Classification of Protein Domains (2014, background): “Fortunately, many examples have shown that analysis of proteins in the context of their distant homologs provides functional clues that advance biological research [15,16,17,18].”
Smad transcription factors. (2005, background): “This conserved lysine-rich sequence forms an -helix right next to the DNA-binding motif in the MH1 domain, not an extended loop as would be structurally required for recognition by importin- (Shi et al. 1998; Chai et al. 2003).”
Zinc as a Gatekeeper of Immune Function (2017, background): “Both BMP and transforming growth factor (TGF)-β signal via the TGF-β receptor and activate Smad signaling molecules containing a zinc-binding motif in the DNA binding domain, thus making Smad signaling a potential target of zinc signaling [303].”