Solution structure of the catalytic domain of GCN5 histone acetyltransferase bound to coenzyme A

• Published in: Nature (London) 1999-07, Vol.400 (6739), p.86-89
• Main Authors: Wagner, Gerhard, Lin, Yingxi, Fletcher, C. Mark, Zhou, Jianxin, Allis, C. David
• Format: Article
• Language: English
• Subjects: Acetyltransferases - chemistry; Acetyltransferases - genetics; Acetyltransferases - metabolism; Alanine - genetics; Amino Acid Sequence; Analytical, structural and metabolic biochemistry; Biochemistry; Biological and medical sciences; Catalysis; Catalytic Domain; Coenzyme A - chemistry; Coenzyme A - metabolism; Deoxyribonucleic acid; DNA; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Genetics; Histone Acetyltransferases; Histones - metabolism; Humanities and Social Sciences; letter; Lysine - metabolism; Macromolecular Substances; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Sequence Data; multidisciplinary; Packaging; Peptides; Point Mutation; Protein Conformation; Protein Structure, Secondary; Proteins; Recombinant Proteins - chemistry; Saccharomyces cerevisiae Proteins; Science; Science (multidisciplinary); Solutions; Tetrahymena; Transferases; Yeasts
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/21922

Gene transcription requires the release of inactive DNA from its packaging of histone proteins. Following the discovery of the first transcription-associated histone acetyltransferase, tetrahymena GCN5, it was shown that yeast GCN5 is recruited to the promoter and causes hyper-acetylation of histones and transcriptional activation of target genes,, establishing a direct connection between histone acetylation and transcriptional activation. Many other important transcription regulators have been found to have histone acetyltransferase activity, including TAFii230/250, p300/CBP and its associated factor PCAF,,,. Here we present the solution structure of the catalytic domain of tGCN5 (residues 47-210) in complex with coenzyme A. The structure contains two domains; the amino-terminal domain is similar to those of other GCN5-related N-acetyltransferases, but the carboxy-terminal domain is not. Coenzyme A binds in a deep hydrophobic pocket between the two domains. Chemical shift changes upon titration with histone H3 peptides indicate a binding site at the domain boundary opposite to the coenzyme A site. The structural data indicate a single-step acetyl-transfer reaction mechanism catalysed by a hydrogen bond to the backbone amide group of leucine 126 and the side-chain carboxyl group of a conserved acidic residue.