NHC Key Laboratory of Cancer Proteomics and Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Key Laboratory of Medical Genetics and College of Life Science, Central South University, Changsha, Hunan 410008, China.
Nucleic Acids Res. 2019 Apr 23;47(7):3752-3764. doi: 10.1093/nar/gkz077.
The FOXC family of transcription factors (FOXC1 and FOXC2) plays essential roles in the regulation of embryonic, ocular, and cardiac development. Mutations and abnormal expression of FOXC proteins are implicated in genetic diseases as well as cancer. In this study, we determined two crystal structures of the DNA-binding domain (DBD) of human FOXC2 protein, in complex with different DNA sites. The FOXC2-DBD adopts the winged-helix fold with helix H3 contributing to all the base specific contacts, while the N-terminus, wing 1, and the C-terminus of FOXC2-DBD all make additional contacts with the phosphate groups of DNA. Our structural, biochemical, and bioinformatics analyses allow us to revise the previously proposed DNA recognition mechanism and provide a model of DNA binding for the FOXC proteins. In addition, our structural analysis and accompanying biochemical assays provide a molecular basis for understanding disease-causing mutations in FOXC1 and FOXC2.
叉头框转录因子家族（FOXC1 和 FOXC2）在胚胎、眼部和心脏发育的调控中发挥着重要作用。FOXC 蛋白的突变和异常表达与遗传疾病以及癌症有关。在这项研究中，我们测定了人 FOXC2 蛋白 DNA 结合域（DBD）与不同 DNA 结合位点复合物的两个晶体结构。FOXC2-DBD 采用翼螺旋结构，螺旋 H3 与所有碱基特异性接触有关，而 FOXC2-DBD 的 N 端、翼 1 和 C 端都与 DNA 的磷酸基团形成额外的接触。我们的结构、生化和生物信息学分析允许我们修改先前提出的 DNA 识别机制，并为 FOXC 蛋白的 DNA 结合提供模型。此外，我们的结构分析和伴随的生化分析为理解 FOXC1 和 FOXC2 致病突变提供了分子基础。
