Fungal Rtt109 histone acetyltransferase is an unexpected structural homolog of metazoan p300/CBP.
Rtt109, also known as KAT11, is a recently characterized fungal-specific histone acetyltransferase (HAT) that modifies histone H3 lysine 56 (H3K56) to promote genome stability. Rtt109 does not show sequence conservation with other known HATs and depends on association with either of two histone chaperones, Asf1 or Vps75, for HAT activity. Here we report the X-ray crystal structure of an Rtt109-acetyl coenzyme A complex and carry out structure-based mutagenesis, combined with in vitro biochemical studies of the Rtt109-Vps75 complex and studies of Rtt109 function in vivo. The Rtt109 structure reveals noteworthy homology to the metazoan p300/CBP HAT domain but exhibits functional divergence, including atypical catalytic properties and mode of cofactor regulation. The structure reveals a buried autoacetylated lysine residue that we show is also acetylated in the Rtt109 protein purified from yeast cells. Implications for understanding histone substrate and chaperone binding by Rtt109 are discussed.
Program in Gene Expression and Regulation, The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Yong
Y
Tang
Marc A
MA
Holbert
Hugo
H
Wurtele
Katrina
K
Meeth
Walter
W
Rocha
Marlene
M
Gharib
Eva
E
Jiang
Pierre
P
Thibault
Alain
A
Verreault
Alain
A
Verrault
Philip A
PA
Cole
Ronen
R
Marmorstein
D000105:Acetyl Coenzyme A / Q000737:chemistry; D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D051548:Histone Acetyltransferases / Q000737:chemistry*; D006657:Histones / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008958:Models, Molecular; D016296:Mutagenesis; D009153:Mutagens / Q000494:pharmacology; D050505:Mutant Proteins / Q000378:metabolism; D017433:Protein Structure, Secondary; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry*; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D050880:p300-CBP Transcription Factors / Q000737:chemistry*
D006657:Histones; D009153:Mutagens; D050505:Mutant Proteins; D029701:Saccharomyces cerevisiae Proteins; D000105:Acetyl Coenzyme A; D051548:Histone Acetyltransferases; C517120:Rtt109 protein, S cerevisiae; D050880:p300-CBP Transcription Factors; D008239:Lysine