The structural basis of protein acetylation by the p300/CBP transcriptional coactivator

Xin Liu, Ling Wang, Kehao Zhao, Paul R. Thompson, Yousang Hwang, Ronen Marmorstein () and Philip A. Cole ()
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Xin Liu: Program in Gene Expression and Regulation, The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA
Ling Wang: Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA
Kehao Zhao: Program in Gene Expression and Regulation, The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA
Paul R. Thompson: Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA
Yousang Hwang: Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA
Ronen Marmorstein: Program in Gene Expression and Regulation, The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA
Philip A. Cole: Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA

Nature, 2008, vol. 451, issue 7180, 846-850

Abstract: Abstract The transcriptional coactivator p300/CBP (CREBBP) is a histone acetyltransferase (HAT) that regulates gene expression by acetylating histones and other transcription factors. Dysregulation of p300/CBP HAT activity contributes to various diseases including cancer1,2,3,4. Sequence alignments, enzymology experiments and inhibitor studies on p300/CBP have led to contradictory results about its catalytic mechanism and its structural relation to the Gcn5/PCAF and MYST HATs5,6,7,8,9. Here we describe a high-resolution X-ray crystal structure of a semi-synthetic heterodimeric p300 HAT domain in complex with a bi-substrate inhibitor, Lys-CoA. This structure shows that p300/CBP is a distant cousin of other structurally characterized HATs, but reveals several novel features that explain the broad substrate specificity and preference for nearby basic residues. Based on this structure and accompanying biochemical data, we propose that p300/CBP uses an unusual ‘hit-and-run’ (Theorell–Chance) catalytic mechanism that is distinct from other characterized HATs. Several disease-associated mutations can also be readily accounted for by the p300 HAT structure. These studies pave the way for new epigenetic therapies involving modulation of p300/CBP HAT activity.

Date: 2008
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DOI: 10.1038/nature06546

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