Specific Acetylation Patterns of H2A.Z Form Transient Interactions with the BPTF Bromodomain.

Specific Acetylation Patterns of H2A.Z Form Transient Interactions with the BPTF Bromodomain.
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H2A.Z 的特定乙酰化模式与 BPTF 布罗莫结构域形成瞬时相互作用。

DOI:
10.1021/acs.biochem.7b00648
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发表时间:
2017
期刊:
影响因子:
2.9
通讯作者:
Pomerantz,WilliamCK
Pomerantz,WilliamCK
中科院分区:
生物学3区
文献类型:
--
作者:
Perell,GabriellaT;Mishra,NeerajK;Sudhamalla,Babu;Ycas,PeterD;Islam,Kabirul;Pomerantz,WilliamCK

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Post-translational lysine acetylation of histone tails affects both chromatin accessibility and recruitment of multifunctional bromodomain-containing proteins for modulating transcription. The bromodomain- and PHD finger-containing transcription factor (BPTF) regulates transcription but has also been implicated in high gene expression levels in a variety of cancers. In this report, the histone variant H2A.Z, which replaces H2A in chromatin, is evaluated for its affinity for BPTF with a specific recognition pattern of acetylated lysine residues of the N-terminal tail region. Although BPTF immunoprecipitates H2A.Z-containing nucleosomes, a direct interaction with its bromodomain has not been reported. Using protein-observed fluorine nuclear magnetic resonance (PrOF NMR) spectroscopy, we identified a diacetylation of H2A.Z on lysine residues 4 and 11, with the highest affinity for BPTF with aKdof 780 μM. A combination of subsequent1H NMR Carr–Purcell–Meiboom–Gill experiments and photo-cross-linking further confirmed the specificity of the diacetylation pattern at lysines 4 and 11. Because of an adjacent PHD domain, this transient interaction may contribute to a higher-affinity bivalent interaction. Further evaluation of specificity toward a set of bromodomains, including two BET bromodomains (Brd4 and BrdT) and twoPlasmodium falciparumbromodomains, resulted in one midmicromolar affinity binder,PfGCN5 (Kd= 650 μM). With these biochemical experiments, we have identified a direct interaction of histone H2A.Z with bromodomains with a specific acetylation pattern that further supports the role of H2A.Z in epigenetic regulation.
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