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The ATAD2 bromodomain binds different acetylation marks on the histone H4 in similar fuzzy complexes


Langini, Cassiano; Caflisch, Amedeo; Vitalis, Andreas (2017). The ATAD2 bromodomain binds different acetylation marks on the histone H4 in similar fuzzy complexes. Journal of Biological Chemistry, 292(40):16734-16745.

Abstract

Bromodomains are protein modules adopting conserved helix bundle folds. Some bromodomain-containing proteins, such as ATPase family AAA domain-containing protein 2 (ATAD2), isoform A, have attracted much interest because they are overexpressed in many types of cancer. Bromodomains bind to acetylated lysine residues on histone tails and thereby facilitate the reading of the histone code. Epigenetic regulators in general have been implicated as indicators, mediators, or causes of a large number of diseases and disorders. To interfere with or modulate these processes, it is therefore of fundamental interest to understand the molecular mechanisms by which epigenetic regulation occurs. Here, we present results from molecular dynamics simulations of a doubly acetylated histone H4 peptide bound to the bromodomain of ATAD2 (hereafter referred to as ATAD2A). These simulations revealed how the flexibility of ATAD2A's major loop, the so-called ZA loop, creates an adaptable interface that preserves the disorder of both peptide and loop in the bound state. We further demonstrate that the binding involves an almost identical average pattern of interactions irrespective of which acetyl mark is inserted into the pocket. In conjunction with a likely mechanism of electrostatically driven recruitment, our simulation results highlight how the bromodomain is built toward promiscuous binding with low specificity. In conclusion, the simulations indicate that disorder and electrostatic steering function jointly to recruit ATAD2A to the histone core and that these fuzzy interactions may promote cooperativity between nearby epigenetic marks.

Abstract

Bromodomains are protein modules adopting conserved helix bundle folds. Some bromodomain-containing proteins, such as ATPase family AAA domain-containing protein 2 (ATAD2), isoform A, have attracted much interest because they are overexpressed in many types of cancer. Bromodomains bind to acetylated lysine residues on histone tails and thereby facilitate the reading of the histone code. Epigenetic regulators in general have been implicated as indicators, mediators, or causes of a large number of diseases and disorders. To interfere with or modulate these processes, it is therefore of fundamental interest to understand the molecular mechanisms by which epigenetic regulation occurs. Here, we present results from molecular dynamics simulations of a doubly acetylated histone H4 peptide bound to the bromodomain of ATAD2 (hereafter referred to as ATAD2A). These simulations revealed how the flexibility of ATAD2A's major loop, the so-called ZA loop, creates an adaptable interface that preserves the disorder of both peptide and loop in the bound state. We further demonstrate that the binding involves an almost identical average pattern of interactions irrespective of which acetyl mark is inserted into the pocket. In conjunction with a likely mechanism of electrostatically driven recruitment, our simulation results highlight how the bromodomain is built toward promiscuous binding with low specificity. In conclusion, the simulations indicate that disorder and electrostatic steering function jointly to recruit ATAD2A to the histone core and that these fuzzy interactions may promote cooperativity between nearby epigenetic marks.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:6 October 2017
Deposited On:07 Nov 2017 14:46
Last Modified:01 Nov 2018 01:31
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
Additional Information:Correction to Langini et al. 292 (40): 16734 https://doi.org/10.1074/jbc.AAC117.000630
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1074/jbc.M117.786350
Related URLs:https://www.zora.uzh.ch/id/eprint/148148/
PubMed ID:28798233
Project Information:
  • : FunderSNSF
  • : Grant ID315230_149897
  • : Project TitleComputational studies of ligand binding and allostery

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