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Structural basis for genome wide recognition of 5-bp GC motifs by SMAD transcription factors

Author

Listed:
  • Pau Martin-Malpartida

    (Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology)

  • Marta Batet

    (Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology)

  • Zuzanna Kaczmarska

    (EMBL Grenoble)

  • Regina Freier

    (Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology)

  • Tiago Gomes

    (Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology)

  • Eric Aragón

    (Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology)

  • Yilong Zou

    (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
    Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center
    Center for the Science of Therapeutics, Broad Institute of MIT and Harvard)

  • Qiong Wang

    (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center)

  • Qiaoran Xi

    (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
    MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University)

  • Lidia Ruiz

    (Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology)

  • Angela Vea

    (Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology)

  • José A. Márquez

    (EMBL Grenoble)

  • Joan Massagué

    (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center)

  • Maria J. Macias

    (Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology
    ICREA)

Abstract

Smad transcription factors activated by TGF-β 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-β 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-β and BMP pathways.

Suggested Citation

  • Pau Martin-Malpartida & Marta Batet & Zuzanna Kaczmarska & Regina Freier & Tiago Gomes & Eric Aragón & Yilong Zou & Qiong Wang & Qiaoran Xi & Lidia Ruiz & Angela Vea & José A. Márquez & Joan Massagué , 2017. "Structural basis for genome wide recognition of 5-bp GC motifs by SMAD transcription factors," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02054-6
    DOI: 10.1038/s41467-017-02054-6
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