Crystal structure of the histone acetyltransferase domain of the human PCAF transcriptional regulator bound to coenzyme A

The human E300/CBP-associating factor, PCAF, mediates transcriptional activ ation through its ability to acetylate nucleosomal histone substrates as we ll as transcriptional activators such as p53. We have determined the 2.3 An gstrom crystal structure of the histone acetyltransferase (HAT) domain of P CAF bound to coenzyme A. The structure reveals a central protein core assoc iated with coenzyme A binding and a pronounced cleft that sits over the pro tein core and is flanked on opposite sides by the N- and C-terminal protein segments. A correlation of the structure with the extensive mutagenesis da ta for PCAF and the homologous yeast GCN5 protein implicates the cleft and the N- and C-terminal protein segments as playing an important role in hist one substrate binding, and a glutamate residue in the protein core as playi ng an essential catalytic role. A structural comparison with the coenzyme-b ound forms of the related N-acetyltransferases, HAT1 (yeast histone acetylt ransferase 1) and SmAAT (Serratia marcescens aminoglycoside 3-N-acetyltrans ferase), suggests the mode of substrate binding and catalysis by these enzy mes and establishes a paradigm for understanding the structure-function rel ationships of other enzymes that acetylate histones and transcriptional reg ulators to promote activated transcription.