Okuda Masahiko, Tsunaka Yasuo, Nishimura Yoshifumi
Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-Cho, Tsurumi-Ku, Yokohama, 230-0045 Japan.
Graduate School of Integrated Sciences for Life, Hiroshima University, 1-4-4 Kagamiyama, Higashi-Hiroshima, 739-8528 Japan.
Biophys Rev. 2022 Nov 18;14(6):1449-1472. doi: 10.1007/s12551-022-01014-9. eCollection 2022 Dec.
Advances in structural analysis by cryogenic electron microscopy (cryo-EM) and X-ray crystallography have revealed the tertiary structures of various chromatin-related proteins, including transcription factors, RNA polymerases, nucleosomes, and histone chaperones; however, the dynamic structures of intrinsically disordered regions (IDRs) in these proteins remain elusive. Recent studies using nuclear magnetic resonance (NMR), together with molecular dynamics (MD) simulations, are beginning to reveal dynamic structures of the general transcription factor TFIIH complexed with target proteins including the general transcription factor TFIIE, the tumor suppressor p53, the cell cycle protein DP1, the DNA repair factors XPC and UVSSA, and three RNA polymerases, in addition to the dynamics of histone tails in nucleosomes and histone chaperones. In complexes of TFIIH, the PH domain of the p62 subunit binds to an acidic string formed by the IDR in TFIIE, p53, XPC, UVSSA, DP1, and the RPB6 subunit of three RNA polymerases by a common interaction mode, namely extended string-like binding of the IDR on the positively charged surface of the PH domain. In the nucleosome, the dynamic conformations of the N-tails of histones H2A and H2B are correlated, while the dynamic conformations of the N-tails of H3 and H4 form a histone tail network dependent on their modifications and linker DNA. The acidic IDRs of the histone chaperones of FACT and NAP1 play important roles in regulating the accessibility to histone proteins in the nucleosome.
低温电子显微镜（cryo-EM）和X射线晶体学在结构分析方面的进展揭示了各种染色质相关蛋白的三级结构，包括转录因子、RNA聚合酶、核小体和组蛋白伴侣；然而，这些蛋白中内在无序区域（IDR）的动态结构仍然难以捉摸。最近使用核磁共振（NMR）以及分子动力学（MD）模拟的研究开始揭示通用转录因子TFIIH与靶蛋白（包括通用转录因子TFIIE、肿瘤抑制因子p53、细胞周期蛋白DP1、DNA修复因子XPC和UVSSA以及三种RNA聚合酶）形成的复合物的动态结构，此外还揭示了核小体和组蛋白伴侣中组蛋白尾巴的动态变化。在TFIIH复合物中，p62亚基的PH结构域通过一种常见的相互作用模式，即IDR在PH结构域带正电表面上的延伸串状结合，与TFIIE、p53、XPC、UVSSA、DP1以及三种RNA聚合酶的RPB6亚基中的IDR形成的酸性串结合。在核小体中，组蛋白H2A和H2B的N端尾巴的动态构象相互关联，而H3和H4的N端尾巴的动态构象形成了一个依赖于其修饰和连接DNA的组蛋白尾巴网络。FACT和NAP1的组蛋白伴侣的酸性IDR在调节核小体中组蛋白的可及性方面发挥着重要作用。
