Tallant Cynthia, Valentini Erica, Fedorov Oleg, Overvoorde Lois, Ferguson Fleur M, Filippakopoulos Panagis, Svergun Dmitri I, Knapp Stefan, Ciulli Alessio
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK; Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford OX3 7FZ, UK.
European Molecular Biology Laboratory, Hamburg Outstation, c/o DESY, Notkestrasse 85, 22603 Hamburg, Germany.
Structure. 2015 Jan 6;23(1):80-92. doi: 10.1016/j.str.2014.10.017. Epub 2014 Dec 18.
Binding of the chromatin remodeling complex NoRC to RNA complementary to the rDNA promoter mediates transcriptional repression. TIP5, the largest subunit of NoRC, is involved in recruitment to rDNA by interactions with promoter-bound TTF-I, pRNA, and acetylation of H4K16. TIP5 domains that recognize posttranslational modifications on histones are essential for recruitment of NoRC to chromatin, but how these reader modules recognize site-specific histone tails has remained elusive. Here, we report crystal structures of PHD zinc finger and bromodomains from human TIP5 and BAZ2B in free form and bound to H3 and/or H4 histones. PHD finger functions as an independent structural module in recognizing unmodified H3 histone tails, and the bromodomain prefers H3 and H4 acetylation marks followed by a key basic residue, KacXXR. Further low-resolution analyses of PHD-bromodomain modules provide molecular insights into their trans histone tail recognition, required for nucleosome recruitment and transcriptional repression of the NoRC complex.
染色质重塑复合物NoRC与rDNA启动子互补的RNA结合介导转录抑制。TIP5是NoRC最大的亚基，通过与启动子结合的TTF-I、pRNA相互作用以及H4K16的乙酰化参与募集到rDNA。识别组蛋白翻译后修饰的TIP5结构域对于NoRC募集到染色质至关重要，但这些读取模块如何识别位点特异性组蛋白尾巴仍不清楚。在这里，我们报告了人TIP5和BAZ2B的PHD锌指和溴结构域的晶体结构，它们以游离形式存在并与H3和/或H4组蛋白结合。PHD指在识别未修饰的H3组蛋白尾巴时作为一个独立的结构模块发挥作用，并且溴结构域更喜欢H3和H4的乙酰化标记，后面跟着一个关键的碱性残基KacXXR。对PHD-溴结构域模块的进一步低分辨率分析为它们跨组蛋白尾巴识别提供了分子见解，这是NoRC复合物核小体募集和转录抑制所必需的。
