Coordination of Di-Acetylated Histone Ligands by the ATAD2 Bromodomain.
Coordination of Di-Acetylated Histone Ligands by the ATAD2 Bromodomain.
复制标题
DOI：
10.3390/ijms22179128
复制
发表时间：
2021-08-24
影响因子：
5.6
通讯作者：
Glass KC
中科院分区：
文献类型：
--
作者：
Evans CM;Phillips M;Malone KL;Tonelli M;Cornilescu G;Cornilescu C;Holton SJ;Gorjánácz M;Wang L;Carlson S;Gay JC;Nix JC;Demeler B;Markley JL;Glass KC
ATPase家族的AAA结构域蛋白2 （AAA domain containing protein 2, ATAD2）溴域（BRD）具有由4个α-螺旋组成的典型溴域结构。ATAD2作为雄激素和雌激素受体以及MYC和E2F转录因子的共激活因子。ATAD2也在DNA复制过程中发挥作用，识别新合成的组蛋白。此外，ATAD2在乳腺癌、肺癌、胃癌、子宫内膜癌、肾癌和前列腺癌等多种癌症中均上调。此外，在许多类型的癌症中，ATAD2的上调与预后不良密切相关，这使得ATAD2溴结构域成为癌症治疗的创新靶点。在这项研究中，我们描述了ATAD2溴结构域对组蛋白乙酰赖氨酸修饰的识别。通过核磁共振波谱（NMR）和x射线晶体学获得的组蛋白尾部和ATAD2溴域之间形成的复合物的残基特异性信息，阐明了结合袋内的关键残基，这些残基参与了二乙酰化组蛋白尾部的配位。分析性超离心、核磁共振弛豫数据和等温滴定量热法进一步证实了功能活性ATAD2溴结构域与二乙酰化组蛋白配体配合物的单体状态。总的来说，我们描述了ATAD2 BRD对组蛋白尾部的识别，并说明了一个乙酰赖氨酸基团主要由保守的天冬酰胺（N1064）、裂谷热货架残基和灵活的ZA环参与。第二个乙酰赖氨酸基团的配位也发生在相同的结合袋内，但本质上是由独特的疏水和静电相互作用控制的，这使得二乙酰赖氨酸组蛋白的配位比以前假设的更特异性。
The ATPase Family, AAA domain-containing protein 2 (ATAD2) bromodomain (BRD) has a canonical bromodomain structure consisting of four α-helices. ATAD2 functions as a co-activator of the androgen and estrogen receptors as well as the MYC and E2F transcription factors. ATAD2 also functions during DNA replication, recognizing newly synthesized histones. In addition, ATAD2 is shown to be up-regulated in multiple forms of cancer including breast, lung, gastric, endometrial, renal, and prostate. Furthermore, up-regulation of ATAD2 is strongly correlated with poor prognosis in many types of cancer, making the ATAD2 bromodomain an innovative target for cancer therapeutics. In this study, we describe the recognition of histone acetyllysine modifications by the ATAD2 bromodomain. Residue-specific information on the complex formed between the histone tail and the ATAD2 bromodomain, obtained through nuclear magnetic resonance spectroscopy (NMR) and X-ray crystallography, illustrates key residues lining the binding pocket, which are involved in coordination of di-acetylated histone tails. Analytical ultracentrifugation, NMR relaxation data, and isothermal titration calorimetry further confirm the monomeric state of the functionally active ATAD2 bromodomain in complex with di-acetylated histone ligands. Overall, we describe histone tail recognition by ATAD2 BRD and illustrate that one acetyllysine group is primarily engaged by the conserved asparagine (N1064), the “RVF” shelf residues, and the flexible ZA loop. Coordination of a second acetyllysine group also occurs within the same binding pocket but is essentially governed by unique hydrophobic and electrostatic interactions making the di-acetyllysine histone coordination more specific than previously presumed.
登录
查看更多内容
影响因子：
3.4
作者：
Cao, Weiming;Demeler, Borries
通讯作者：
Demeler, Borries
影响因子：
5.7
作者：
Flynn, E. Megan;Huang, Oscar W.;Cochran, Andrea G.
通讯作者：
Cochran, Andrea G.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1002/anie.201603928
发表时间：
2016-09-12
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Bamborough P;Chung CW;Demont EH;Furze RC;Bannister AJ;Che KH;Diallo H;Douault C;Grandi P;Kouzarides T;Michon AM;Mitchell DJ;Prinjha RK;Rau C;Robson S;Sheppard RJ;Upton R;Watson RJ
通讯作者：
Watson RJ