Greber Basil J, Nguyen Thi Hoang Duong, Fang Jie, Afonine Pavel V, Adams Paul D, Nogales Eva
California Institute for Quantitative Biology (QB3), University of California, Berkeley, California 94720, USA.
Molecular Biophysics and Integrative Bio-Imaging Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
Nature. 2017 Sep 21;549(7672):414-417. doi: 10.1038/nature23903. Epub 2017 Sep 13.
Human transcription factor IIH (TFIIH) is part of the general transcriptional machinery required by RNA polymerase II for the initiation of eukaryotic gene transcription. Composed of ten subunits that add up to a molecular mass of about 500 kDa, TFIIH is also essential for nucleotide excision repair. The seven-subunit TFIIH core complex formed by XPB, XPD, p62, p52, p44, p34, and p8 is competent for DNA repair, while the CDK-activating kinase subcomplex, which includes the kinase activity of CDK7 as well as the cyclin H and MAT1 subunits, is additionally required for transcription initiation. Mutations in the TFIIH subunits XPB, XPD, and p8 lead to severe premature ageing and cancer propensity in the genetic diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy, highlighting the importance of TFIIH for cellular physiology. Here we present the cryo-electron microscopy structure of human TFIIH at 4.4 Å resolution. The structure reveals the molecular architecture of the TFIIH core complex, the detailed structures of its constituent XPB and XPD ATPases, and how the core and kinase subcomplexes of TFIIH are connected. Additionally, our structure provides insight into the conformational dynamics of TFIIH and the regulation of its activity.
人类转录因子IIH（TFIIH）是RNA聚合酶II启动真核基因转录所需的通用转录机制的一部分。TFIIH由十个亚基组成，总分子量约为500 kDa，对核苷酸切除修复也至关重要。由XPB、XPD、p62、p52、p44、p34和p8形成的七亚基TFIIH核心复合物具有DNA修复能力，而转录起始还需要包含CDK7激酶活性以及细胞周期蛋白H和MAT1亚基的CDK激活激酶亚复合物。TFIIH亚基XPB、XPD和p8的突变会导致色素性干皮病、科凯恩综合征和毛发硫营养不良等遗传性疾病出现严重早衰和癌症倾向，这突出了TFIIH对细胞生理学的重要性。在此，我们展示了分辨率为4.4 Å的人类TFIIH的冷冻电子显微镜结构。该结构揭示了TFIIH核心复合物的分子结构、其组成的XPB和XPD ATP酶的详细结构，以及TFIIH的核心和激酶亚复合物是如何连接的。此外，我们的结构还深入了解了TFIIH的构象动力学及其活性调节。
