Crystal structure of the histone acetyltransferase domain of the human PCAF transcriptional regulator bound to coenzyme A.
The human p300/CBP-associating factor, PCAF, mediates transcriptional activation through its ability to acetylate nucleosomal histone substrates as well as transcriptional activators such as p53. We have determined the 2.3 A crystal structure of the histone acetyltransferase (HAT) domain of PCAF bound to coenzyme A. The structure reveals a central protein core associated with coenzyme A binding and a pronounced cleft that sits over the protein core and is flanked on opposite sides by the N- and C-terminal protein segments. A correlation of the structure with the extensive mutagenesis data 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 histone substrate binding, and a glutamate residue in the protein core as playing an essential catalytic role. A structural comparison with the coenzyme-bound forms of the related N-acetyltransferases, HAT1 (yeast histone acetyltransferase 1) and SmAAT (Serratia marcescens aminoglycoside 3-N-acetyltransferase), suggests the mode of substrate binding and catalysis by these enzymes and establishes a paradigm for understanding the structure-function relationships of other enzymes that acetylate histones and transcriptional regulators to promote activated transcription.
Clements
A
A
The Wistar Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Rojas
J R
JR
Trievel
R C
RC
Wang
L
L
Berger
S L
SL
Marmorstein
R
R
D000107:Acetylation; D000123:Acetyltransferases / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D002384:Catalysis; D003065:Coenzyme A / Q000737:chemistry / Q000378:metabolism*; D017124:Conserved Sequence; D003460:Crystallization; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins; D005656:Fungal Proteins / Q000737:chemistry / Q000378:metabolism; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism; D051548:Histone Acetyltransferases; D006657:Histones / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D029701:Saccharomyces cerevisiae Proteins; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D003065:Coenzyme A; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D018698:Glutamic Acid; D051548:Histone Acetyltransferases; D006657:Histones; D011494:Protein Kinases; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C501392:GCN5 protein, S cerevisiae; D000099224:p300-CBP-Associated Factor