Structural basis for genome wide recognition of 5-bp GC motifs by SMAD transcription factors
The main TGF-β signal transduction mechanism is the Smad pathway, with the Smad transcription factors being responsible for the transmission of the signals from the membrane to the nucleus.We have identified a new 5bp consensus binding sequence for TGF-beta and BMP activated Smad proteins as well as for Smad4. The interactions have been characterized using X-ray and other biophysical and molecular biology techniques. The key contacts between the protein and the DNA are highlighted in the figure.
Martin-Malpartida P, Batet M, Kaczmarska Z, Freier R, Gomes T, Aragon E, Zou Y, Wang Q, Xi Q, Ruiz L, Vea A, Marquez JA, Massague J, Macias MJ.
Nat Commun 2017 Dec; 8: 2070.
Smad transcription factors activated by TGF-beta or by BMP receptors form trimeric complexes with Smad4 to target specific genes for cell fate regulation. The CAGAC motif has been considered as the main binding element for Smad2/3/4, whereas Smad1/5/8 have been thought to preferentially bind GC-rich elements. However, chromatin immunoprecipitation analysis in embryonic stem cells showed extensive binding of Smad2/3/4 to GC-rich cis-regulatory elements. Here, we present the structural basis for specific binding of Smad3 and Smad4 to GC-rich motifs in the goosecoid promoter, a nodal-regulated differentiation gene. The structures revealed a 5-bp consensus sequence GGC(GC)|(CG) as the binding site for both TGF-beta and BMP-activated Smads and for Smad4. These 5GC motifs are highly represented as clusters in Smad-bound regions genome-wide. Our results provide a basis for understanding the functional adaptability of Smads in different cellular contexts, and their dependence on lineage-determining transcription factors to target specific genes in TGF-beta and BMP pathways.
PubMed: 29234012. Doi: 10.1038/s41467-017-02054-6. free PMC article
