Molecular basis for the autoregulation of the protein acetyl transferase Rtt109.
Rtt109 is a protein acetyltransferase (PAT) that is responsible for the acetylation of lysine-56 of histone 3 (H3K56) in yeast. H3K56 acetylation has been implicated in the weakening of the interaction between the histone core and the surrounding DNA in the nucleosomal particle. Rtt109, in cooperation with various histone chaperones, promotes genomic stability and is required for resistance to DNA damaging agents. Here, we present the crystal structure of Rtt109 in complex with acetyl-CoA at a 2.0-A resolution. Rtt109 consists of a core PAT domain, which binds the acetyl-CoA cofactor. A second domain, the activation domain, is tightly associated with the PAT domain. Autoacetylation of lysine-290 within the activation domain is required for stabilizing the interaction between the two domains and is essential for catalysis. Biochemical analysis demonstrates the requirement of a loop within the PAT domain for the binding of the histone chaperone Vps75, and mutational analysis identifies key residues for catalysis. We propose a model in which the autoacetylation of Rtt109 is crucial for the regulation of its catalytic activity.
Stavropoulos
Pete
P
Laboratory of Cell Biology, Rockefeller University and Howard Hughes Medical Institute, 1230 York Avenue, New York, NY 10065, USA.
Nagy
Vivien
V
Blobel
Günter
G
Hoelz
André
A
D000105:Acetyl Coenzyme A / Q000737:chemistry* / Q000378:metabolism; D000107:Acetylation; D002384:Catalysis; D018360:Crystallography, X-Ray; D004795:Enzyme Stability; D051548:Histone Acetyltransferases / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D006706:Homeostasis; D018832:Molecular Chaperones / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology
D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins; C525548:Vps75 protein, S cerevisiae; D000105:Acetyl Coenzyme A; D051548:Histone Acetyltransferases; C517120:Rtt109 protein, S cerevisiae