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

被引：0
作者：
Xin Liu
Ling Wang
Kehao Zhao
Paul R. Thompson
Yousang Hwang
Ronen Marmorstein
Philip A. Cole
机构：
[1] Program in Gene Expression and Regulation,Department of Chemistry
[2] The Wistar Institute,Department of Pharmacology and Molecular Sciences
[3] 3601 Spruce Street,undefined
[4] Philadelphia,undefined
[5] Pennsylvania 19104,undefined
[6] USA ,undefined
[7] University of Pennsylvania,undefined
[8] Philadelphia,undefined
[9] Pennsylvania 19104,undefined
[10] USA,undefined
[11] Johns Hopkins University School of Medicine,undefined
[12] 725 North Wolfe Street,undefined
[13] Baltimore,undefined
[14] Maryland 21205,undefined
[15] USA,undefined
[16] Present addresses: Novartis Institute for Biomedical Research,undefined
[17] Cambridge,undefined
[18] Massachusetts 02139,undefined
[19] USA (K.Z.); Department of Chemistry and Biochemistry,undefined
[20] University of South Carolina,undefined
[21] 631 Sumter Street,undefined
[22] Columbia,undefined
[23] South Carolina 29208,undefined
[24] USA (P.R.T.),undefined
来源：
Nature | 2008年 / 451卷
关键词：
D O I：
暂无
中图分类号：
学科分类号：
摘要：
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.
引用
收藏
页码：846 / 850
页数：4
相关论文
共 58 条
[1]  
Goodman RH(2000)CBP/p300 in cell growth, transformation, and development Genes Dev. 14 1553-1577
[2]  
Smolik S(1996)The transcriptional coactivators p300 and CBP are histone acetyltransferases Cell 87 953-959
[3]  
Ogryzko VV(1996)The CBP co-activator is a histone acetyltransferase Nature 384 641-643
[4]  
Schiltz RL(2004)p300/CBP and cancer Oncogene 23 4225-4231
[5]  
Russanova V(1998)The acetyltransferase activity of CBP stimulates transcription EMBO J. 17 2886-2893
[6]  
Howard BH(2002)Acetyltransferase machinery conserved in p300/CBP-family proteins Oncogene 21 2253-2260
[7]  
Nakatani Y(2002)Structure of the GCN5 histone acetyltransferase bound to a bisubstrate inhibitor Proc. Natl Acad. Sci. USA 99 14065-14070
[8]  
Bannister AJ(2000)HATs off: selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF Mol. Cell 5 589-595
[9]  
Kouzarides T(2001)Transcriptional coactivator protein p300. Kinetic characterization of its histone acetyltransferase activity J. Biol. Chem. 276 33721-33729
[10]  
Iyer NG(2004)Regulation of the p300 HAT domain via a novel activation loop Nature Struct. Mol. Biol. 11 308-315
123456