Binding specificity and function of the SWI/SNF subunit SMARCA4 bromodomain interaction with acetylated histone H3K14.
Binding specificity and function of the SWI/SNF subunit SMARCA4 bromodomain interaction with acetylated histone H3K14.
复制标题
DOI：
10.1016/j.jbc.2021.101145
复制
发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Rose RB
中科院分区：
文献类型：
--
作者：
Enríquez P;Krajewski K;Strahl BD;Rothbart SB;Dowen RH;Rose RB
溴结构域(BD)是一种保守的阅读器模块，与组蛋白上的乙酰化赖氨酸残基结合。虽然关于这些结构域的体外性质已经了解了很多，但对它们在染色质复合体中的功能知之甚少。SWI/SNF染色质重塑复合体调节转录并有助于DNA损伤修复。SWI/SNF亚单位的突变与许多癌症有关。在这里，我们证明了秀丽线虫SMARCA4/BRG1的BD，一个核心的SWI/SNF亚基，识别组蛋白H3(H3K14ac)的乙酰化赖氨酸14，类似于它的智人直系同源基因。我们从CeSMARCA4 BD-H3K14ac络合物的1.29？分辨率晶体结构中鉴定了SMARCA4与乙酰化组蛋白多肽的相互作用。值得注意的是，大多数与组蛋白多肽接触的SMARCA4 BD残基与其他含有第VIII族溴域的蛋白是保守的。基于溴域同源物之间的结合特异性是保守的前提，我们提出了结合口袋外的环残基位置接触残基识别H3K14ac序列。CRISPR-Cas9介导的SMARCA4 BD突变在体外取消了H3K14ac结合，对体内线虫的存活率或生理功能几乎没有影响。然而，SMARCA4 BD突变和SWI/SNF辅助亚单位PBRM-1的敲除结合在一起会导致动物严重的发育缺陷。总之，我们在体内证明了SWI/SNF溴域的一个重要功能，并在表观遗传读取器中检测到了调节染色质重塑的潜在冗余。这些发现对开发治疗癌症和其他疾病的小分子BD抑制剂具有重要意义。
Bromodomains (BD) are conserved reader modules that bind acetylated lysine residues on histones. Although much has been learned regarding the in vitro properties of these domains, less is known about their function within chromatin complexes. SWI/SNF chromatin-remodeling complexes modulate transcription and contribute to DNA damage repair. Mutations in SWI/SNF subunits have been implicated in many cancers. Here we demonstrate that the BD of Caenorhabditis elegans SMARCA4/BRG1, a core SWI/SNF subunit, recognizes acetylated lysine 14 of histone H3 (H3K14ac), similar to its Homo sapiens ortholog. We identify the interactions of SMARCA4 with the acetylated histone peptide from a 1.29 Å-resolution crystal structure of the CeSMARCA4 BD–H3K14ac complex. Significantly, most of the SMARCA4 BD residues in contact with the histone peptide are conserved with other proteins containing family VIII bromodomains. Based on the premise that binding specificity is conserved among bromodomain orthologs, we propose that loop residues outside of the binding pocket position contact residues to recognize the H3K14ac sequence. CRISPR-Cas9-mediated mutations in the SMARCA4 BD that abolish H3K14ac binding in vitro had little or no effect on C. elegans viability or physiological function in vivo. However, combining SMARCA4 BD mutations with knockdown of the SWI/SNF accessory subunit PBRM-1 resulted in severe developmental defects in animals. In conclusion, we demonstrated an essential function for the SWI/SNF bromodomain in vivo and detected potential redundancy in epigenetic readers in regulating chromatin remodeling. These findings have implications for the development of small-molecule BD inhibitors to treat cancers and other diseases.
登录
查看更多内容
影响因子：
10.5
作者：
Dowen RH;Breen PC;Tullius T;Conery AL;Ruvkun G
通讯作者：
Ruvkun G
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
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/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
影响因子：
9.2
作者：
Fuchs, Stephen M.;Krajewski, Krzysztof;Baker, Richard W.;Miller, Victoria L.;Strahl, Brian D.
通讯作者：
Strahl, Brian D.