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Nature. 2018 Oct;562(7728):538-544. doi: 10.1038/s41586-018-0621-1. Epub 2018 Oct 15.

Transcription factor dimerization activates the p300 acetyltransferase.

Author information

1
European Molecular Biology Laboratory, Grenoble, France.
2
Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Göttingen, Germany.
3
Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, UK.
4
CNRS UMR 5309, INSERM U1209, Université Grenoble Alpes, Institute for Advanced Biosciences, Grenoble, France.
5
Université Grenoble Alpes, INSERM U1042, HP2 Laboratory, Grenoble, France.
6
Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University in St. Louis, St. Louis, MO, USA.
7
European Molecular Biology Laboratory, Grenoble, France. daniel.panne@le.ac.uk.
8
Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, UK. daniel.panne@le.ac.uk.

Abstract

The transcriptional co-activator p300 is a histone acetyltransferase (HAT) that is typically recruited to transcriptional enhancers and regulates gene expression by acetylating chromatin. Here we show that the activation of p300 directly depends on the activation and oligomerization status of transcription factor ligands. Using two model transcription factors, IRF3 and STAT1, we demonstrate that transcription factor dimerization enables the trans-autoacetylation of p300 in a highly conserved and intrinsically disordered autoinhibitory lysine-rich loop, resulting in p300 activation. We describe a crystal structure of p300 in which the autoinhibitory loop invades the active site of a neighbouring HAT domain, revealing a snapshot of a trans-autoacetylation reaction intermediate. Substrate access to the active site involves the rearrangement of an autoinhibitory RING domain. Our data explain how cellular signalling and the activation and dimerization of transcription factors control the activation of p300, and therefore explain why gene transcription is associated with chromatin acetylation.

PMID:
30323286
DOI:
10.1038/s41586-018-0621-1

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