Post-translational modifications in DNA topoisomerase 2α highlight the role of a eukaryote-specific residue in the ATPase domain.
Post-translational modifications in DNA topoisomerase 2α highlight the role of a eukaryote-specific residue in the ATPase domain.
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DOI：
10.1038/s41598-018-27606-8
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发表时间：
2018-06-18
影响因子：
4.6
通讯作者：
Lamour V
中科院分区：
文献类型：
--
作者：
Bedez C;Lotz C;Batisse C;Broeck AV;Stote RH;Howard E;Pradeau-Aubreton K;Ruff M;Lamour V
2型DNA拓扑异构酶（Top2）是参与DNA复制、染色体凝聚和分离以及基因转录的关键蛋白质复合物的关键组分。Top2被发现是抗癌药物的主要靶点，这导致了人们对它们的功能和生理作用以及它们的分子结构的深入研究。据报道，翻译后修饰会影响Top2酶活性，特别是哺乳动物Top2α亚型的活性。在这项研究中，我们确定了磷酸化，并首次在真核表达系统中产生的人Top2α亚型乙酰化位点。结构分析表明，乙酰化位点聚集在同源二聚体的催化结构域，而磷酸化位点位于负责核定位的C-末端结构域。ATP酶结构域中真核生物特异性K168残基的生化分析表明，乙酰化通过调节二聚化影响调节ATP水解的关键位置。我们的研究结果表明，乙酰化的特定位点参与人类Top2的变构调节可能提供了一种机制，调节其催化活性。
Type 2 DNA topoisomerases (Top2) are critical components of key protein complexes involved in DNA replication, chromosome condensation and segregation, as well as gene transcription. The Top2 were found to be the main targets of anticancer agents, leading to intensive efforts to understand their functional and physiological role as well as their molecular structure. Post-translational modifications have been reported to influence Top2 enzyme activities in particular those of the mammalian Top2α isoform. In this study, we identified phosphorylation, and for the first time, acetylation sites in the human Top2α isoform produced in eukaryotic expression systems. Structural analysis revealed that acetylation sites are clustered on the catalytic domains of the homodimer while phosphorylation sites are located in the C-terminal domain responsible for nuclear localization. Biochemical analysis of the eukaryotic-specific K168 residue in the ATPase domain shows that acetylation affects a key position regulating ATP hydrolysis through the modulation of dimerization. Our findings suggest that acetylation of specific sites involved in the allosteric regulation of human Top2 may provide a mechanism for modulation of its catalytic activity.
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影响因子：
4.8
作者：
Hammonds, TR;Maxwell, A
通讯作者：
Maxwell, A
DOI：
10.1002/prot.340040208
发表时间：
1988-01-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
BRUNGER, AT;KARPLUS, M
通讯作者：
KARPLUS, M
影响因子：
2.6
作者：
GIETZ, RD;SCHIESTL, RH;WOODS, RA
通讯作者：
WOODS, RA
影响因子：
4.8
作者：
AUSTIN, CA;MARSH, KL;FISHER, LM
通讯作者：
FISHER, LM
影响因子：
4.1
作者：
Aoyama, M;Grabowski, DR;Ganapathi, R
通讯作者：
Ganapathi, R