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PMID: 21555453 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Structural basis and specificity of acetylated transcription factor GATA1 recognition by BET family bromodomain protein Brd3.

Molecular and cellular biology ·Vol. 31 ·No. 13 ·2011-07-00 ·Pages 2632-40

Gamsjaeger R, Webb SR, Lamonica JM, Billin A, Blobel GA, Mackay JP

Abstract

Recent data demonstrate that small synthetic compounds specifically targeting bromodomain proteins can modulate the expression of cancer-related or inflammatory genes. Although these studies have focused on the ability of bromodomains to recognize acetylated histones, it is increasingly becoming clear that histone-like modifications exist on other important proteins, such as transcription factors. However, our understanding of the molecular mechanisms through which these modifications modulate protein function is far from complete. The transcription factor GATA1 can be acetylated at lysine residues adjacent to the zinc finger domains, and this acetylation is essential for the normal chromatin occupancy of GATA1. We have recently identified the bromodomain-containing protein Brd3 as a cofactor that interacts with acetylated GATA1 and shown that this interaction is essential for the targeting of GATA1 to chromatin. Here we describe the structural basis for this interaction. Our data reveal for the first time the molecular details of an interaction between a transcription factor bearing multiple acetylation modifications and its cognate recognition module. We also show that this interaction can be inhibited by an acetyllysine mimic, highlighting the importance of further increasing the specificity of compounds that target bromodomain and extraterminal (BET) bromodomains in order to fully realize their therapeutic potential.

MeSH Terms
Acetylation Amino Acid Sequence GATA1 Transcription Factor/antagonists & inhibitors,chemistry,genetics,metabolism Humans Hydrophobic and Hydrophilic Interactions Lysine/chemistry,genetics,metabolism Molecular Sequence Data Protein Structure, Secondary RNA-Binding Proteins/chemistry,genetics,metabolism Transcription Factors
Chemicals
BRD3 protein, human GATA1 Transcription Factor GATA1 protein, human RNA-Binding Proteins Transcription Factors Lysine
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Gamsjaeger Roland
School of Molecular Bioscience, University of Sydney, Sydney, NSW 2006, Australia.
Webb Sarah R
Lamonica Janine M
Billin Andrew
Blobel Gerd A
Mackay Joel P
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.05413-11
Published
2011-07-00
Epub
2011-00-09
Pages
2632-40
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC3133386
Subset
IM
Grants
NIDDK NIH HHS · R01 DK054937 · United States
NHLBI NIH HHS · T32 HL007971 · United States
NHLBI NIH HHS · T32 HL007971-07 · United States
External Links
PubMed source DOI: 10.1128/MCB.05413-11 PMC Full Text View journal details
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