Abstract
TGIF1 is a multifunctional protein that represses TGF-β-activated transcription by interacting with Smad2-Smad4 complexes. We found that the complex structure of TGIF1-HD bound to the TGACA motif revealed a combined binding mode that involves the HD core and the major groove, on the one hand, and the amino-terminal (N-term) arm and the minor groove of the DNA, on the other. We also show that TGIF1-HD interacts with the MH1 domain of Smad proteins, thereby indicating that TGIF1-HD is also a protein-binding domain. Moreover, the formation of the HD-MH1 complex partially hinders the DNA-binding site of the complex, preventing the efficient interaction of TGIF1-HD with DNA. We propose that the binding of the TGIF1 C-term to the Smad2-MH2 domain brings both the HD and MH1 domain into close proximity. This local proximity facilitates the interaction of these DNA-binding domains, thus strengthening the formation of the protein complex versus DNA binding. Once the protein complex has been formed, the TGIF1-Smad system would be released from promoters/enhancers, thereby illustrating one of the mechanisms used by TGIF1 to exert its function as an active repressor of Smad-induced TGF-β signaling.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Sequence
-
Animals
-
Binding Sites
-
Cloning, Molecular
-
Crystallography, X-Ray
-
DNA / chemistry*
-
DNA / genetics
-
DNA / metabolism
-
Escherichia coli / genetics
-
Escherichia coli / metabolism
-
Gene Expression
-
Gene Expression Regulation
-
Genetic Vectors / chemistry
-
Genetic Vectors / metabolism
-
Homeodomain Proteins / chemistry*
-
Homeodomain Proteins / genetics
-
Homeodomain Proteins / metabolism
-
Humans
-
Models, Molecular
-
Nucleotide Motifs
-
Protein Binding
-
Protein Conformation, alpha-Helical
-
Protein Conformation, beta-Strand
-
Protein Interaction Domains and Motifs
-
Recombinant Proteins / chemistry
-
Recombinant Proteins / genetics
-
Recombinant Proteins / metabolism
-
Repressor Proteins / chemistry*
-
Repressor Proteins / genetics
-
Repressor Proteins / metabolism
-
Sequence Alignment
-
Sequence Homology, Amino Acid
-
Signal Transduction
-
Smad2 Protein / chemistry*
-
Smad2 Protein / genetics
-
Smad2 Protein / metabolism
-
Smad4 Protein / chemistry*
-
Smad4 Protein / genetics
-
Smad4 Protein / metabolism
-
Transforming Growth Factor beta / chemistry*
-
Transforming Growth Factor beta / genetics
-
Transforming Growth Factor beta / metabolism
Substances
-
Homeodomain Proteins
-
Recombinant Proteins
-
Repressor Proteins
-
SMAD2 protein, human
-
SMAD4 protein, human
-
Smad2 Protein
-
Smad4 Protein
-
TGIF1 protein, human
-
Transforming Growth Factor beta
-
DNA