Histone modification plays an important role in various biological processes, including gene expression regulation. Bromodomain, as one of histone readers, recognizes specifically the ε-N-lysine acetylation (KAc) of histone. Although the bromodomains and histone acetylation sites of Trypanosoma brucei (T. brucei), a lethal parasite responsible for sleeping sickness in human and nagana in cattle, have been identified, how acetylated histones are recognized by bromodomains is still unknown. Here, the bromodomain factor 2 (TbBDF2) from T. brucei was identified to be located in the nucleolus and bind to the hyperacetylated N-terminus of H2AZ which dimerizes with H2BV. The bromodomain of TbBDF2 (TbBDF2-BD) displays a conserved fold that comprises a left-handed bundle of four α-helices (αZ, αA, αB, αC), linked by loop regions of variable length (ZA and BC loops), which form the KAc-binding pocket. NMR chemical shift perturbation further revealed that TbBDF2-BD binds to the hyperacetylated N-terminus of H2AZ through its KAc-binding pocket. By structure-based virtual screening combining with the ITC experiment, a small molecule compound, GSK2801, was shown to have high affinity to TbBDF2-BD. GSK2801 and the hyperacetylated N-terminus of H2AZ have similar binding sites on TbBDF2-BD. In addition, GSK2801 competitively inhibits the hyperacetylated N-terminus of H2AZ binding to TbBDF2-BD. After treatment of GSK2801, cell growth was inhibited and localization of TbBDF2 was disrupted. Our results report a novel bromodomain-histone recognition by TbBDF2-BD and imply that TbBDF2 may serve as a potential chemotherapeutic target for the treatment of trypanosomiasis.
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November 2017
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A 3D rendering of a mitochondrion. In this issue of the Biochemical Journal, Monteuuis et al. report that a conserved mammalian mitochondrial isoform of acetyl-CoA carboxylase ACC1 provides the malonyl-CoA essential for mitochondrial biogenesis in tandem with the mitochondrial malonyl-CoA synthetase ACSF3; see pages 3783–3797 for details.
Research Article|
November 09 2017
Recognition of hyperacetylated N-terminus of H2AZ by TbBDF2 from Trypanosoma brucei
Xiao Yang;
Xiao Yang
1School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
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Xuelei Wu;
Xuelei Wu
1School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
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Jiahai Zhang;
Jiahai Zhang
1School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
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Xuecheng Zhang;
Xuecheng Zhang
2School of Life Sciences, Anhui University, Hefei, Anhui, China
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Chao Xu;
Chao Xu
1School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
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Shanhui Liao;
1School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
Correspondence: Shanhui Liao (ajsod@mail.ustc.edu.cn) or Xiaoming Tu (xmtu@ustc.edu.cn)
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Xiaoming Tu
1School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
Correspondence: Shanhui Liao (ajsod@mail.ustc.edu.cn) or Xiaoming Tu (xmtu@ustc.edu.cn)
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Publisher: Portland Press Ltd
Received:
August 07 2017
Revision Received:
October 05 2017
Accepted:
October 09 2017
Accepted Manuscript online:
October 12 2017
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2017
Biochem J (2017) 474 (22): 3817–3830.
Article history
Received:
August 07 2017
Revision Received:
October 05 2017
Accepted:
October 09 2017
Accepted Manuscript online:
October 12 2017
Citation
Xiao Yang, Xuelei Wu, Jiahai Zhang, Xuecheng Zhang, Chao Xu, Shanhui Liao, Xiaoming Tu; Recognition of hyperacetylated N-terminus of H2AZ by TbBDF2 from Trypanosoma brucei. Biochem J 15 November 2017; 474 (22): 3817–3830. doi: https://doi.org/10.1042/BCJ20170619
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