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Crystal structure of TALE homeobox domain transcription factor TGIF1 double alanine mutant bound to its consensus DNA
Structural highlights
Disease[TGIF1_HUMAN] Septopreoptic holoprosencephaly;Semilobar holoprosencephaly;Lobar holoprosencephaly;Alobar holoprosencephaly;Midline interhemispheric variant of holoprosencephaly;Microform holoprosencephaly. The disease is caused by mutations affecting the gene represented in this entry. Function[TGIF1_HUMAN] Binds to a retinoid X receptor (RXR) responsive element from the cellular retinol-binding protein II promoter (CRBPII-RXRE). Inhibits the 9-cis-retinoic acid-dependent RXR alpha transcription activation of the retinoic acid responsive element. Active transcriptional corepressor of SMAD2. Links the nodal signaling pathway to the bifurcation of the forebrain and the establishment of ventral midline structures. May participate in the transmission of nuclear signals during development and in the adult, as illustrated by the down-modulation of the RXR alpha activities. Publication Abstract from PubMedTGIF1 is a multifunctional protein that represses TGF-beta-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-beta signaling. TGIF1 homeodomain interacts with Smad MH1 domain and represses TGF-beta signaling.,Guca E, Sunol D, Ruiz L, Konkol A, Cordero J, Torner C, Aragon E, Martin-Malpartida P, Riera A, Macias MJ Nucleic Acids Res. 2018 Jul 28. pii: 5061025. doi: 10.1093/nar/gky680. PMID:30060237[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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