DNA-binding mechanism of the Hippo pathway transcription factor TEAD4

Article metrics


TEA domain (TEAD) family transcription factors are key regulators in development, tissue homeostasis and cancer progression. TEAD4 acts as a critical downstream effector of the evolutionarily conserved Hippo signaling pathway. The well-studied oncogenic protein YAP forms a complex with TEAD4 to regulate gene transcription; so does the tumor suppressor VGLL4. Although it is known that TEAD proteins can bind promoter regions of target genes through the TEA domain, the specific and detailed mechanism of DNA recognition by the TEA domain remains partially understood. Here, we report the crystal structure of TEAD4 TEA domain in complex with a muscle-CAT DNA element. The structure revealed extensive interactions between the TEA domain and the DNA duplex involving both the major and minor grooves of DNA helix. The DNA recognition helix, α3 helix, determines the specificity of the TEA domain binding to DNA sequence. Structure-guided biochemical analysis identified two major binding sites on the interface of the TEA domain–DNA complex. Mutation of TEAD4 at either site substantially decreases its occupancy on the promoter region of target genes, and largely impaired YAP-induced TEAD4 transactivation and target gene transcription, leading to inhibition of growth and colony formation of gastric cancer cell HGC-27. Collectively, our work provides a structural basis for understanding the regulatory mechanism of TEAD-mediated gene transcription.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6


  1. 1

    Pobbati AV, Hong W . Emerging roles of TEAD transcription factors and its coactivators in cancers. Cancer Biol Ther 2013; 14: 390–398.

  2. 2

    Xiao JH, Davidson I, Ferrandon D, Rosales R, Vigneron M, Macchi M et al. One cell-specific and three ubiquitous nuclear proteins bind in vitro to overlapping motifs in the domain B1 of the SV40 enhancer. EMBO J 1987; 6: 3005–3013.

  3. 3

    Davidson I, Xiao JH, Rosales R, Staub A, Chambon P . The HeLa cell protein TEF-1 binds specifically and cooperatively to two SV40 enhancer motifs of unrelated sequence. Cell 1988; 54: 931–942.

  4. 4

    Nikovits Jr W, Kuncio G, Ordahl CP . The chicken fast skeletal troponin I gene: exon organization and sequence. Nucleic Acids Res 1986; 14: 3377–3390.

  5. 5

    Mar JH, Ordahl CP . A conserved CATTCCT motif is required for skeletal muscle-specific activity of the cardiac troponin T gene promoter. Proc Natl Acad Sci USA 1988; 85: 6404–6408.

  6. 6

    Mar JH, Ordahl CP . M-CAT binding factor, a novel trans-acting factor governing muscle-specific transcription. Mol Cell Biol 1990; 10: 4271–4283.

  7. 7

    Zhou Y, Huang T, Cheng AS, Yu J, Kang W, To KF . The TEAD family and its oncogenic role in promoting tumorigenesis. Int J Mol Sci 2016; 17. pii: E138.

  8. 8

    Yu FX, Zhao B, Guan KL . Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 2015; 163: 811–828.

  9. 9

    Moroishi T, Hansen CG, Guan KL . The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer 2015; 15: 73–79.

  10. 10

    Pan D . Hippo signaling in organ size control. Genes Dev 2007; 21: 886–897.

  11. 11

    Zhao B, Tumaneng K, Guan KL . The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat Cell Biol 2011; 13: 877–883.

  12. 12

    Meng Z, Moroishi T, Guan KL . Mechanisms of Hippo pathway regulation. Genes Dev 2016; 30: 1–17.

  13. 13

    Mo JS, Meng Z, Kim YC, Park HW, Hansen CG, Kim S et al. Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nat Cell Biol 2015; 17: 500–510.

  14. 14

    Wang W, Xiao ZD, Li X, Aziz KE, Gan B, Johnson RL et al. AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nat Cell Biol 2015; 17: 490–499.

  15. 15

    Zhang W, Gao Y, Li P, Shi Z, Guo T, Li F et al. VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex. Cell Res 2014; 24: 331–343.

  16. 16

    Jiao S, Wang H, Shi Z, Dong A, Zhang W, Song X et al. A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell 2014; 25: 166–180.

  17. 17

    Guo T, Lu Y, Li P, Yin MX, Lv D, Zhang W et al. A novel partner of Scalloped regulates Hippo signaling via antagonizing Scalloped-Yorkie activity. Cell Res 2013; 23: 1201–1214.

  18. 18

    Koontz LM, Liu-Chittenden Y, Yin F, Zheng Y, Yu J, Huang B et al. The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression. Dev Cell 2013; 25: 388–401.

  19. 19

    Vaudin P, Delanoue R, Davidson I, Silber J, Zider A . TONDU (TDU), a novel human protein related to the product of vestigial (vg) gene of Drosophila melanogaster interacts with vertebrate TEF factors and substitutes for Vg function in wing formation. Development 1999; 126: 4807–4816.

  20. 20

    Maeda T, Chapman DL, Stewart AF . Mammalian vestigial-like 2, a cofactor of TEF-1 and MEF2 transcription factors that promotes skeletal muscle differentiation. J Biol Chem 2002; 277: 48889–48898.

  21. 21

    Shi Z, Jiao S, Zhou Z . Structural dissection of Hippo signaling. Acta Biochim Biophys Sin (Shanghai) 2015; 47: 29–38.

  22. 22

    Chen L, Chan SW, Zhang X, Walsh M, Lim CJ, Hong W et al. Structural basis of YAP recognition by TEAD4 in the hippo pathway. Genes Dev 2010; 24: 290–300.

  23. 23

    Li Z, Zhao B, Wang P, Chen F, Dong Z, Yang H et al. Structural insights into the YAP and TEAD complex. Genes Dev 2010; 24: 235–240.

  24. 24

    Pobbati AV, Chan SW, Lee I, Song H, Hong W . Structural and functional similarity between the Vgll1-TEAD and the YAP-TEAD complexes. Structure 2012; 20: 1135–1140.

  25. 25

    Chan P, Han X, Zheng B, DeRan M, Yu J, Jarugumilli GK et al. Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway. Nat Chem Biol 2016; 12: 282–289.

  26. 26

    Noland CL, Gierke S, Schnier PD, Murray J, Sandoval WN, Sagolla M et al. Palmitoylation of TEAD transcription factors is required for their stability and function in Hippo pathway signaling. Structure 2016; 24: 179–186.

  27. 27

    Andrianopoulos A, Timberlake WE . ATTS, a new and conserved DNA binding domain. Plant Cell 1991; 3: 747–748.

  28. 28

    Burglin TR . The TEA domain: a novel, highly conserved DNA-binding motif. Cell 1991; 66: 11–12.

  29. 29

    Anbanandam A, Albarado DC, Nguyen CT, Halder G, Gao X, Veeraraghavan S . Insights into transcription enhancer factor 1 (TEF-1) activity from the solution structure of the TEA domain. Proc Natl Acad Sci USA 2006; 103: 17225–17230.

  30. 30

    Aravind L, Anantharaman V, Balaji S, Babu MM, Iyer LM . The many faces of the helix-turn-helix domain: transcription regulation and beyond. FEMS Microbiol Rev 2005; 29: 231–262.

  31. 31

    Lee DS, Vonrhein C, Albarado D, Raman CS, Veeraraghavan S . A potential structural switch for regulating DNA-binding by TEAD transcription factors. J Mol Biol 2016; 428: 2557–2568.

  32. 32

    Chan SW, Lim CJ, Loo LS, Chong YF, Huang C, Hong W . TEADs mediate nuclear retention of TAZ to promote oncogenic transformation. J Biol Chem 2009; 284: 14347–14358.

  33. 33

    Lim B, Park JL, Kim HJ, Park YK, Kim JH, Sohn HA et al. Integrative genomics analysis reveals the multilevel dysregulation and oncogenic characteristics of TEAD4 in gastric cancer. Carcinogenesis 2014; 35: 1020–1027.

  34. 34

    Otwinowski Z, Minor W . Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol 1997; 276: 307–326.

  35. 35

    Adams PD, Afonine PV, Bunkoczi G, Chen VB, Davis IW, Echols N et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr 2010; 66: 213–221.

  36. 36

    Emsley P, Lohkamp B, Scott WG, Cowtan K . Features and development of Coot. Acta Crystallogr D Biol Crystallogr 2010; 66: 486–501.

  37. 37

    Afonine PV, Grosse-Kunstleve RW, Echols N, Headd JJ, Moriarty NW, Mustyakimov M et al. Towards automated crystallographic structure refinement with phenix.refine. Acta Crystallogr D Biol Crystallogr 2012; 68: 352–367.

Download references


We thank the staff at beamline BL17U of Shanghai Synchrotron Radiation Facility (SSRF) for assistance with data collection. This work was supported by the 973 program of the Ministry of Science and Technology of China (2012CB910204), the National Natural Science Foundation of China (31270808, 31300734, 31470736, 31470868, 31600731, 91442125 and 91542125), the Youth Innovation Promotion Association of Chinese Academy of Sciences, the Knowledge Innovation Program of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (2014KIP202), and the 'Strategic Priority Research Program' of the Chinese Academy of Sciences (XDA12020342 and XDB19020202).

Accession numbers

The structural coordinate of the TEA domain 4–DNA complex was deposited in the PDB under the code 5GZB.

Author information

Correspondence to Z Zhou.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shi, Z., He, F., Chen, M. et al. DNA-binding mechanism of the Hippo pathway transcription factor TEAD4. Oncogene 36, 4362–4369 (2017) doi:10.1038/onc.2017.24

Download citation

Further reading