Regulation of the p300 HAT domain via a novel activation loop.
The transcriptional coactivator p300 is a histone acetyltransferase (HAT) whose function is critical for regulating gene expression in mammalian cells. However, the molecular events that regulate p300 HAT activity are poorly understood. We evaluated autoacetylation of the p300 HAT protein domain to determine its function. Using expressed protein ligation, the p300 HAT protein domain was generated in hypoacetylated form and found to have reduced catalytic activity. This basal catalytic rate was stimulated by autoacetylation of several key lysine sites within an apparent activation loop motif. This post-translational modification and catalytic regulation of p300 HAT activity is conceptually analogous to the activation of most protein kinases by autophosphorylation. We therefore propose that this autoregulatory loop could influence the impact of p300 on a wide variety of signaling and transcriptional events.
Thompson
Paul R
PR
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Wang
Dongxia
D
Wang
Ling
L
Fulco
Marcella
M
Pediconi
Natalia
N
Zhang
Dianzheng
D
An
Woojin
W
Ge
Qingyuan
Q
Roeder
Robert G
RG
Wong
Jiemin
J
Levrero
Massimo
M
Sartorelli
Vittorio
V
Cotter
Robert J
RJ
Cole
Philip A
PA
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation; D000123:Acetyltransferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D017124:Conserved Sequence; D017931:DNA Primers; D004789:Enzyme Activation; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D051548:Histone Acetyltransferases; D007700:Kinetics; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D017931:DNA Primers; D029968:Escherichia coli Proteins; D011994:Recombinant Proteins; D000105:Acetyl Coenzyme A; D000123:Acetyltransferases; D051548:Histone Acetyltransferases