Hippo信号通路下游转录因子复合物YAP-TEAD的结构与功能研究
摘要
Hippo信号通路主要控制细胞的生长、增殖和器官的大小。YAP是该信号通路下游的效应因子,从果蝇到哺乳动物高度保守。YAP能够进入细胞核,与核内的转录因子相互结合,启动下游靶基因的转录。Hippo信号通路一旦被激活,上游激酶磷酸化YAP,被磷酸化的YAP能够与细胞骨架蛋白14-3-3蛋白相互作用,停留在胞质内,不能进入细胞核激活基因转录。
YAP是肿瘤发生的一个调控因子,已经被认为是一个癌基因。在很多肿瘤中发现YAP染色体区域扩增。在结肠癌,肺癌,卵巢癌中,发现YAP在胞质内和细胞核内高表达。
TEAD是细胞核内与YAP结合最主要的转录因子,YAP与TEAD结合后,依赖TEAD中DNA结合功能域,启动下游基因转录。YAP结合TEAD的生物学意义已经越来越清楚了,但两者的三维结构及它们作用的分子机制仍不清楚。
本文以人源的YAP2和TEAD1为研究对象,利用分子克隆,生物化学手段在体外表达纯化两种蛋白质,鉴定出两者的结合区;体外组装稳定的YAP-TEAD复合物,通过离子交换层析和分子筛层析纯化。通过大规模的晶体筛选,然后利用硒代晶体SAD数据解析出复合物结构,最终结构修至2.8(?)。从解出的结构中发现,YAP环绕在TEAD周围,主要通过三个位点与TEAD结合。结合生化分析和细胞实验,发现位点Ⅲ(86-100aa)是YAP与TEAD结合最重要的位置。通过结构,我们阐明了YAP与TEAD相互作用的分子机制,为干扰YAP与TEAD相互作用的药物提供了结构基础。
The Hippo signaling pathway plays an essential role in regulating cell growth, cell proliferation and organ size. YAP, the downstream effector of Hippo signaling pathway, is highly conserved from Drosophila to mammalians. Activation of Hippo signaling initiates a kinase cascade, thereby YAP is phosphorylated by upstream kinase. The phosphorylated YAP supplies a binding site for 14-3-3, and is restrained in cytoplasm. Otherwise, YAP could translocate into nucleus and activate the target genes transcription by binding with transcription factors, like TEAD.
YAP is a key regulator of tumorigenesis and a candidate oncogene amplified in human cancers. Amplification of the chromosome region containing the YAP gene has been reported in several human tumor types. There was strong and diffuse nuclear and cytoplasmic YAP expression in colonic adenocarcinoma, lung adenocarcinoma and ovarian serous cystadenocarcinoma.
Transcription enhancer factors (TEF/TEAD) is the most important binding partner of YAP in the nucleus. YAP and TEAD physically interact and form a functional transcription complex capable of activating the targeting genes. Although YAP and TEAD play important roles in many cellular aspects, the molecular mechanism of YAP mediated TEAD-dependent transcription remains unknown.,
In this thesis, we focus our studies on protein complex of human YAP2 and TEAD1. Molecular biological and biochemistry techniques were used to map their binding interface. The stable complex used for crystallization was assembled in vitro and purified to homogeneity by ion exchange and gel filtration chromatography. The crystal structure of YAP-TEAD complex was solved by SeMet SAD (seleneomethionine single-wavelength anomalous diffraction) and the structure was refined to 2.8 angstrom. In the complex structure, YAP wraps around the globular structure of TEAD and forms extensive interaction via three highly conserved interfaces. We show that the interface three including YAP residues 86-100 is most critical for the complex formation. Our study reveals the biochemical nature of YAP-TEAD interaction and provides a basis for pharmacological intervention of YAP-TEAD hyperactivation in human diseases.
YAP是肿瘤发生的一个调控因子,已经被认为是一个癌基因。在很多肿瘤中发现YAP染色体区域扩增。在结肠癌,肺癌,卵巢癌中,发现YAP在胞质内和细胞核内高表达。
TEAD是细胞核内与YAP结合最主要的转录因子,YAP与TEAD结合后,依赖TEAD中DNA结合功能域,启动下游基因转录。YAP结合TEAD的生物学意义已经越来越清楚了,但两者的三维结构及它们作用的分子机制仍不清楚。
本文以人源的YAP2和TEAD1为研究对象,利用分子克隆,生物化学手段在体外表达纯化两种蛋白质,鉴定出两者的结合区;体外组装稳定的YAP-TEAD复合物,通过离子交换层析和分子筛层析纯化。通过大规模的晶体筛选,然后利用硒代晶体SAD数据解析出复合物结构,最终结构修至2.8(?)。从解出的结构中发现,YAP环绕在TEAD周围,主要通过三个位点与TEAD结合。结合生化分析和细胞实验,发现位点Ⅲ(86-100aa)是YAP与TEAD结合最重要的位置。通过结构,我们阐明了YAP与TEAD相互作用的分子机制,为干扰YAP与TEAD相互作用的药物提供了结构基础。
The Hippo signaling pathway plays an essential role in regulating cell growth, cell proliferation and organ size. YAP, the downstream effector of Hippo signaling pathway, is highly conserved from Drosophila to mammalians. Activation of Hippo signaling initiates a kinase cascade, thereby YAP is phosphorylated by upstream kinase. The phosphorylated YAP supplies a binding site for 14-3-3, and is restrained in cytoplasm. Otherwise, YAP could translocate into nucleus and activate the target genes transcription by binding with transcription factors, like TEAD.
YAP is a key regulator of tumorigenesis and a candidate oncogene amplified in human cancers. Amplification of the chromosome region containing the YAP gene has been reported in several human tumor types. There was strong and diffuse nuclear and cytoplasmic YAP expression in colonic adenocarcinoma, lung adenocarcinoma and ovarian serous cystadenocarcinoma.
Transcription enhancer factors (TEF/TEAD) is the most important binding partner of YAP in the nucleus. YAP and TEAD physically interact and form a functional transcription complex capable of activating the targeting genes. Although YAP and TEAD play important roles in many cellular aspects, the molecular mechanism of YAP mediated TEAD-dependent transcription remains unknown.,
In this thesis, we focus our studies on protein complex of human YAP2 and TEAD1. Molecular biological and biochemistry techniques were used to map their binding interface. The stable complex used for crystallization was assembled in vitro and purified to homogeneity by ion exchange and gel filtration chromatography. The crystal structure of YAP-TEAD complex was solved by SeMet SAD (seleneomethionine single-wavelength anomalous diffraction) and the structure was refined to 2.8 angstrom. In the complex structure, YAP wraps around the globular structure of TEAD and forms extensive interaction via three highly conserved interfaces. We show that the interface three including YAP residues 86-100 is most critical for the complex formation. Our study reveals the biochemical nature of YAP-TEAD interaction and provides a basis for pharmacological intervention of YAP-TEAD hyperactivation in human diseases.
引文
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8. Hunter, T. (1997). Cell 88, 333-346.
9. Rommel, C, Hafen, E. (1998). Curr. Opin. Genet. Dev. 8,412-418.
10. Weinberg, R.A. (1995). Cell 81,323-330.
11. Foley, K.P., Eisenman, R.N. (1999). Biochim. Biophys. Acta 1423, M37-47.
12. Wyllie, A.H., Kerr, J.F, and Currie, A.R. (1980). Int. Rev. Cytol. 68, 251-306.
13. Evan, G., and Littlewood, T. (1998). Science 281, 1317-1322.
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15. Thornberry, N.A, and Lazebnik, Y. (1998). Science 281, 1312-1316.
16. Harris, C.C. (1996). Carcinogenesis 17, 1187-1198.
17. Hayflick, L. (1997). Biochemistry 62,1180-1190.
18. Wright, W.E., Pereira-Smith, O.M., and Shay, J.W. (1989). Mol. Cell. Biol. 9,3088-3092.
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20. Shay, J.W, and Bacchetti, S. (1997). Eur. J. Cancer 33, 787-791.
21. Bryan, T.M, and Cech, T.R. (1999). Curr. Opin. Cell Biol. 11, 318-324.
22. Bryan, T.M, Englezou, A, Gupta, J, Bacchetti, S, and Reddel, R.R. (1995).EMBO J. 14,4240-4248.
23. Bouck, N, Stellmach, V, and Hsu, S.C. (1996). Adv. Cancer Res. 69, 135-174.
24. Hanahan, D, and Folkman, J. (1996). Cell 86, 353-364.
25. Varner, J.A, and Cheresh, D.A. (1996). Curr. Opin. Cell Biol. 8, 724-730.
26. Stetler-Stevenson, W.G. (1999). J. Clin. Invest. 103, 1237-1241.
27. Whitelock, J.M., Murdoch, A.D., Iozzo, R.V., and Underwood, P.A. (1996). J.Biol. Chem. 271, 10079-10086.
28. Sporn, M.B. (1996). Lancet 347, 1377-1381.
29. Aplin, A.E., Howe, A., Alahari, S.K., and Juliano, R.L. (1998). Pharmacol. Rev.50, 197-263.
30. Christofori, G., Naik, P., and Hanahan, D. (1994). Nature 369,414-418.
31. Coussens, L.M., Raymond, W.W., Bergers, G., Laig-Webster, M.Behrendtsen, O.,Werb, Z., Caughey, G.H., and Hanahan, D. (1999). Genes Dev. 13,1382-1397.
32. Harvey, K., and Tapon, N. (2007). Nat. Rev. Cancer 7,182-191.
33. Pan, D. (2007). Genes Dev. 15, 886-897..
34. Saucedo, L.J, and Edgar, B.A. (2007). Nat. Rev. Mol. Cell Biol. 8, 613-621.
35. Fausto, N., Campbell, J.S., and Riehle, K.J. (2006). Hepatology 43, S45-S53.
36. Eagle, H, and Levine, E.M. (1967). Nature 213, 1102-1106.
37. Hanahan, D., and Weinberg, R.A. (2000). Cell 100, 57-70.
38. Camargo, F.D., Gokhale, S., Johnnidis, J.B., Fu, D., Bell, G.W., Jaenisch, R., and Brummelkamp, T.R. (2007). Curr. Biol. 17, 2054-2060.
39. Dong, J., Feldmann, G., Huang, J., Wu, S., Zhang, N., Comerford, S.A., Gayyed,M.F, Anders, R.A., Maitra, A., and Pan, D. (2007). Cell 130,1120-1133.
40. Zhao, B., Wei, X., Li, W., Udan, R.S., Yang, Q., Kim, J., Xie, J., Ikenoue, T., Yu,J., Li, L, et al. (2007). Genes Dev. 21, 2747-2761.
41. Justice, R.W., Zilian, O., Woods, D.F., Noll, M., and Bryant, P.J. (1995). Genes Dev. 9, 534-546.
42. Tapon, N., Harvey, K.F., Bell, D.W., Wahrer, D.C., Schiripo, T.A., Haber, D.A.,and Hariharan, I.K. (2002). Cell 110,467-478.
43. Wu, S., Huang, J., Dong, J, and Pan, D. (2003). Cell 114, 445-456.
44. Lai, Z.C., Wei, X., Shimizu, T., Ramos, E., Rohrbaugh, M., Nikolaidis, N., Ho,L.L., and Li, Y. (2005). Cell 120, 675-685.
45. Scheel, H., and Hofmann, K. (2003). Curr. Biol. 13, R899-R900.
46. Callus, B.A., Verhagen, A.M., and Vaux, D.L. (2006). FEBS J. 273,4264-4276.
47. Bennett, F.C., and Harvey, K.F. (2006). Curr. Biol. 16, 2101-2110.
48. Cho, E., Feng, Y., Rauskolb, C., Maitra, S., Fehon, R., and Irvine, K.D. (2006).Nat. Genet. 38, 1142-1150.
49. Katherine Striedinger, Scott R. VandenBerg, Gilson S. Baia, Michael W.McDermott,David H. Gutmann and Anita Lal.,(2008). Neoplasia 10 (11) 1204-1212.
50. Mahoney, P. A. et al. (1991). Cell 67, 853-868.
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