title: Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling.
abstract: The Smad family of proteins, which are frequently targeted by tumorigenic mutations in cancer, mediate TGF-beta signaling from cell membrane to nucleus. The crystal structure of a Smad3 MH1 domain bound to an optimal DNA sequence determined at 2.8 A resolution reveals a novel DNA-binding motif. In the crystals, base-specific DNA recognition is provided exclusively by a conserved 11-residue beta hairpin that is embedded in the major groove of DNA. A surface loop region, to which tumorigenic mutations map, has been identified as a functional surface important for Smad activity. This structure establishes a framework for understanding how Smad proteins may act in concert with other transcription factors in the regulation of TGF-beta-responsive genes.
authors.affiliation: Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, New Jersey 08544, USA. ygshi@princeton.edu
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.forename: Y F
authors.initials: YF
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Jayaraman
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.forename: J
authors.initials: J
authors.lastname: Massagué
authors.forename: N P
authors.initials: NP
authors.lastname: Pavletich
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003460:Crystallization; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D051900:Smad3 Protein; D015534:Trans-Activators / Q000737:chemistry*; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D010446:Peptide Fragments; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D004247:DNA