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Phosphorylation-dependent BRD4 dimerization and implications for therapeutic inhibition of BET family proteins.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Malvezzi, Francesca 
Stubbs, Christopher J 
Jowitt, Thomas A 
Dale, Ian L 
Guo, Xieyang 

Abstract

Bromodomain-containing protein 4 (BRD4) is an epigenetic reader and oncology drug target that regulates gene transcription through binding to acetylated chromatin via bromodomains. Phosphorylation by casein kinase II (CK2) regulates BRD4 function, is necessary for active transcription and is involved in resistance to BRD4 drug inhibition in triple-negative breast cancer. Here, we provide the first biophysical analysis of BRD4 phospho-regulation. Using integrative structural biology, we show that phosphorylation by CK2 modulates the dimerization of human BRD4. We identify two conserved regions, a coiled-coil motif and the Basic-residue enriched Interaction Domain (BID), essential for the BRD4 structural rearrangement, which we term the phosphorylation-dependent dimerization domain (PDD). Finally, we demonstrate that bivalent inhibitors induce a conformational change within BRD4 dimers in vitro and in cancer cells. Our results enable the proposal of a model for BRD4 activation critical for the characterization of its protein-protein interaction network and for the development of more specific therapeutics.

Description

Funder: AstraZeneca


Funder: AstraZeneca postdoc fund

Keywords

Casein Kinase II, Cell Cycle Proteins, Gene Expression Regulation, Humans, Phosphorylation, Transcription Factors

Journal Title

Commun Biol

Conference Name

Journal ISSN

2399-3642
2399-3642

Volume Title

4

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research UK (C6946/A24843)
Wellcome Trust (203144/Z/16/Z)
Wellcome Trust (203144/A/16/Z)
Cancer Research UK (17001)