The BRPF1 bromodomain is a molecular reader of di-acetyllysine.
The BRPF1 bromodomain is a molecular reader of di-acetyllysine.
复制标题
BRPF1溴结构域是二乙酰透析的分子读取器。
DOI：
10.1016/j.crstbi.2020.05.001
复制
发表时间：
2020
影响因子：
2.8
通讯作者：
Glass KC
中科院分区：
文献类型：
--
作者：
Obi JO;Lubula MY;Cornilescu G;Henrickson A;McGuire K;Evans CM;Phillips M;Boyson SP;Demeler B;Markley JL;Glass KC
含溴结构域的蛋白质通常是染色质修饰复合物的一部分，其活性可导致人类癌症、炎症和神经系统疾病的基因表达发生改变。 Bromodomain-PHD 指蛋白 1 (BRPF1) 是 MOZ（单核细胞白血病锌指蛋白）HAT（组蛋白乙酰转移酶）复合物的一部分，该复合物与已知导致急性髓系白血病 (AML) 发展的染色体易位相关。 BRPF1 包含染色质读取器结构域的独特组合，包括由锌指节（PZP 结构域）分隔的两个植物同源结构域 (PHD) 指、一个溴结构域和一个脯氨酸-色氨酸-色氨酸-脯氨酸 (PWWP) 结构域。已知 BRPF1 通过其溴结构域识别 N 末端组蛋白尾部区域上的乙酰化赖氨酸残基，从而将 MOZ HAT 复合物募集到染色质。然而，组蛋白的 N 末端可能含有多种乙酰化修饰，并且尚不清楚其他标记如何影响溴结构域向染色质的募集。在这里，我们将 BRPF1 溴结构域鉴定为组蛋白 H4 上二乙酰赖氨酸修饰的选择性读取器。我们使用 ITC 测定来表征二乙酰化组蛋白配体与 BRPF1 溴结构域的结合，发现该结构域优先与组蛋白肽 H4K5acK8ac 和 H4K5acK12ac 结合。分析超速离心 (AUC) 实验表明 BRPF1 溴结构域的单体状态与二乙酰化组蛋白配体协调。 NMR 化学位移扰动研究以及结合和突变分析揭示了溴结构域结合口袋的非规范区域，这些区域对于组蛋白尾部识别非常重要。总之，我们的研究结果提供了关于翻译后修饰的组合作用如何调节 BRPF1 溴结构域结合和特异性的关键信息。
Bromodomain-containing proteins are often part of chromatin-modifying complexes, and their activity can lead to altered expression of genes that drive cancer, inflammation and neurological disorders in humans. Bromodomain-PHD finger protein 1 (BRPF1) is part of the MOZ (monocytic leukemic zinc-finger protein) HAT (histone acetyltransferase) complex, which is associated with chromosomal translocations known to contribute to the development of acute myeloid leukemia (AML). BRPF1 contains a unique combination of chromatin reader domains including two plant homeodomain (PHD) fingers separated by a zinc knuckle (PZP domain), a bromodomain, and a proline-tryptophan-tryptophan-proline (PWWP) domain. BRPF1 is known to recruit the MOZ HAT complex to chromatin by recognizing acetylated lysine residues on the N-terminal histone tail region through its bromodomain. However, histone proteins can contain several acetylation modifications on their N-terminus, and it is unknown how additional marks influence bromodomain recruitment to chromatin. Here, we identify the BRPF1 bromodomain as a selective reader of di-acetyllysine modifications on histone H4. We used ITC assays to characterize the binding of di-acetylated histone ligands to the BRPF1 bromodomain and found that the domain binds preferentially to histone peptides H4K5acK8ac and H4K5acK12ac. Analytical ultracentrifugation (AUC) experiments revealed that the monomeric state of the BRPF1 bromodomain coordinates di-acetylated histone ligands. NMR chemical shift perturbation studies, along with binding and mutational analyses, revealed non-canonical regions of the bromodomain-binding pocket that are important for histone tail recognition. Together, our findings provide critical information on how the combinatorial action of post-translational modifications can modulate BRPF1 bromodomain binding and specificity.
登录
查看更多内容
影响因子：
5.7
作者：
Flynn, E. Megan;Huang, Oscar W.;Cochran, Andrea G.
通讯作者：
Cochran, Andrea G.
影响因子：
2.9
作者：
Champagne, Karen S.;Piscitelli, Elise;Francklyn, Christopher S.
通讯作者：
Francklyn, Christopher S.
影响因子：
2.9
作者：
Gay, Jamie C.;Eckenroth, Brian E.;Glass, Karen C.
通讯作者：
Glass, Karen C.
影响因子：
30.8
作者：
Dulak, Austin M.;Stojanov, Petar;Peng, Shouyong;Lawrence, Michael S.;Fox, Cameron;Stewart, Chip;Bandla, Santhoshi;Imamura, Yu;Schumacher, Steven E.;Shefler, Erica;McKenna, Aaron;Carter, Scott L.;Cibulskis, Kristian;Sivachenko, Andrey;Saksena, Gordon;Voet, Douglas;Ramos, Alex H.;Auclair, Daniel;Thompson, Kristin;Sougnez, Carrie;Onofrio, Robert C.;Guiducci, Candace;Beroukhim, Rameen;Zhou, Zhongren;Lin, Lin;Lin, Jules;Reddy, Rishindra;Chang, Andrew;Landrenau, Rodney;Pennathur, Arjun;Ogino, Shuji;Luketich, James D.;Golub, Todd R.;Gabriel, Stacey B.;Lander, Eric S.;Beer, David G.;Godfrey, Tony E.;Getz, Gad;Bass, Adam J.
通讯作者：
Bass, Adam J.
影响因子：
2.4
作者：
Brookes, Emre;Demeler, Borries
通讯作者：
Demeler, Borries