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

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  • Xin Liu

    (Program in Gene Expression and Regulation, The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA
    University of Pennsylvania, 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
    Present addresses: Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA (K.Z.); Department of Chemistry and Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, USA (P.R.T.))

  • Paul R. Thompson

    (Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA
    Present addresses: Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA (K.Z.); Department of Chemistry and Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, USA (P.R.T.))

  • 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
    University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA)

  • Philip A. Cole

    (Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA)

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.

Suggested Citation

  • Xin Liu & Ling Wang & Kehao Zhao & Paul R. Thompson & Yousang Hwang & Ronen Marmorstein & Philip A. Cole, 2008. "The structural basis of protein acetylation by the p300/CBP transcriptional coactivator," Nature, Nature, vol. 451(7180), pages 846-850, February.
    • Handle: RePEc:nat:nature:v:451:y:2008:i:7180:d:10.1038_nature06546
    DOI: 10.1038/nature06546
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    Cited by:

    1. Ji Min Lee & Henrik M. Hammarén & Mikhail M. Savitski & Sung Hee Baek, 2023. "Control of protein stability by post-translational modifications," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Di Yu & Yingying Liang & Claudia Kim & Anbalagan Jaganathan & Donglei Ji & Xinye Han & Xuelan Yang & Yanjie Jia & Ruirui Gu & Chunyu Wang & Qiang Zhang & Ka Lung Cheung & Ming-Ming Zhou & Lei Zeng, 2023. "Structural mechanism of BRD4-NUT and p300 bipartite interaction in propagating aberrant gene transcription in chromatin in NUT carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Masaki Kikuchi & Satoshi Morita & Masatoshi Wakamori & Shin Sato & Tomomi Uchikubo-Kamo & Takehiro Suzuki & Naoshi Dohmae & Mikako Shirouzu & Takashi Umehara, 2023. "Epigenetic mechanisms to propagate histone acetylation by p300/CBP," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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