Structure of the Brd4 ET domain bound to a C-terminal motif from gamma-retroviral integrases reveals a conserved mechanism of interaction

Crowe Brandon L.; Larue Ross C.; Yuan ChunhuaHess SonjaKvaratskhelia MamukaFoster Mark P.

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Structure of the Brd4 ET domain bound to a C-terminal motif from gamma-retroviral integrases reveals a conserved mechanism of interaction

机译：Structure of the Brd4 ET domain bound to a C-terminal motif from gamma-retroviral integrases reveals a conserved mechanism of interaction

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The bromodomain and extraterminal domain (BET) protein family are promising therapeutic targets for a range of diseases linked to transcriptional activation, cancer, viral latency, and viral integration. Tandem bromodomains selectively tether BET proteins to chromatin by engaging cognate acetylated histone marks, and the extraterminal (ET) domain is the focal point for recruiting a range of cellular and viral proteins. BET proteins guide gamma-retroviral integration to transcription start sites and enhancers through bimodal interaction with chromatin and the gamma-retroviral integrase (IN). We report the NMR-derived solution structure of the Brd4 ET domain bound to a conserved peptide sequence from the C terminus of murine leukemia virus (MLV) IN. The complex reveals a proteinprotein interaction governed by the binding-coupled folding of disordered regions in both interacting partners to form a wellstructured intermolecular three-stranded beta sheet. In addition, we show that a peptide comprising the ET binding motif (EBM) of MLV IN can disrupt the cognate interaction of Brd4 with NSD3, and that substitutions of Brd4 ET residues essential for binding MLV IN also impair interaction of Brd4 with a number of cellular partners involved in transcriptional regulation and chromatin remodeling. This suggests that gamma-retroviruses have evolved the EBM to mimic a cognate interaction motif to achieve effective integration in host chromatin. Collectively, our findings identify key structural features of the ET domain of Brd4 that allow for interactions with both cellular and viral proteins.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2016年第8期|2086-2091|共6页
作者
Crowe Brandon L.; Larue Ross C.; Yuan ChunhuaHess SonjaKvaratskhelia MamukaFoster Mark P.;
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作者单位

Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA;

CALTECH, Proteome Explorat Lab, Pasadena, CA 91125 USA;

Ohio State Univ, Ctr Retrovirus Res, Columbus, OH 43210 USAOhio State Univ, Campus Chem Instrument Ctr, Columbus, OH 43210 USA;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
protein-protein interaction; BET family transcription factor; retroviral integration; ET binding motif (EBM);

Structure of the Brd4 ET domain bound to a C-terminal motif from gamma-retroviral integrases reveals a conserved mechanism of interaction

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