DNA-binding mechanism of the Hippo pathway transcription factor TEAD4
DNA-binding mechanism of the Hippo pathway transcription factor TEAD4
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Hippo途径转录因子TEAD4的DNA结合机制
DOI：
10.1038/onc.2017.24
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发表时间：
2017-07-27
期刊：
影响因子：
8
通讯作者：
Zhou, Z.
中科院分区：
文献类型：
--
作者：
Shi, Z.;He, F.;Zhou, Z.
TEA结构域（TEAD）家族转录因子是发育、组织稳态和癌症进展的关键调节因子。TEAD 4作为进化保守的Hippo信号通路的关键下游效应子。研究充分的致癌蛋白雅普与TEAD 4形成复合物以调节基因转录;肿瘤抑制因子VGLL 4也是如此。虽然已知TEAD蛋白可以通过TEA结构域结合靶基因的启动子区，但TEA结构域识别DNA的具体和详细机制仍不完全清楚。在这里，我们报告的晶体结构的TEAD 4 TEA结构域与肌肉CAT DNA元件的复合物。该结构揭示了TEA结构域和DNA双链体之间的广泛相互作用，涉及DNA螺旋的大沟和小沟。DNA识别螺旋α3螺旋决定了TEA结构域与DNA序列结合的特异性。结构指导的生化分析确定了两个主要的结合位点的TEA结构域-DNA复合物的界面上。TEAD 4的两个突变位点均显著降低了其在靶基因启动子区的占有率，并极大地削弱了YAP诱导的TEAD 4反式激活和靶基因转录，导致胃癌细胞HGC-27的生长和集落形成受到抑制。总的来说，我们的工作为理解TEAD介导的基因转录的调控机制提供了结构基础。
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.