The crystal structure of Capicua HMG-box domain complexed with the ETV5-DNA and its implications for Capicua-mediated cancers
The crystal structure of Capicua HMG-box domain complexed with the ETV5-DNA and its implications for Capicua-mediated cancers
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DOI：
10.1111/febs.15008
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发表时间：
2019-08-01
期刊：
影响因子：
5.4
通讯作者：
Song, Ji-Joon
中科院分区：
文献类型：
--
作者：
Lee, Hyeongseok;Song, Ji-Joon
Capicua（CIC）是一种转录抑制因子，在受体酪氨酸激酶（RTK）信号通路下游发挥作用。在CIC中的HMG盒DNA结合结构域中发现的体细胞突变与几种癌症如少突胶质细胞瘤、少突星形细胞瘤和腺癌有关。然而，CIC的DNA结合的分子基础和在癌症中发现的体细胞突变对DNA结合的影响尚未研究。在这里，我们报告了CIC的HMG盒结构域与其靶DNA，Ets易位变体5（ETV5）的启动子复合的晶体结构。结构表明HMG盒结构域具有L形结构，并识别导致DNA弯曲的小沟。我们的结构与电泳迁移率变动分析（EMSA）相结合，揭示了癌症相关的突变HMG盒域废除与DNA的相互作用。这些结果提供了CIC的DNA结合的分子洞察力，并揭示了致癌突变对DNA结合的影响。
Capicua (CIC) is a transcriptional repressor and functions downstream of the receptor tyrosine kinase (RTK) signaling pathway. Somatic mutations found in the HMG-box DNA binding domain in CIC have been implicated in several cancers such as oligodendroglioma, oligoastrocytoma, and adenocarcinoma. However, the molecular basis of the DNA binding of CIC and the effect of the somatic mutations found in cancers on DNA binding have not been investigated. Here, we report the crystal structure of the HMG-box domain of CIC complexed with its target DNA, the promoter of Ets Translocation Variant 5 (ETV5). The structure shows that the HMG-box domain has an L-shaped structure and recognizes the minor groove leading to DNA bending. Our structure combined with an electrophoretic mobility shift assay (EMSA) revealed that cancer-associated mutations in the HMG-box domain abrogate the interaction with DNA. These results provide the molecular insight into the DNA binding of CIC and reveal the effects of carcinogenic mutations on DNA binding.