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Published August 26, 2008 | Published + Supplemental Material
Journal Article Open

Molecular basis for the autoregulation of the protein acetyl transferase Rtt109

Abstract

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-Å 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.

Additional Information

© 2008 National Academy of Sciences. Contributed by Günter Blobel, June 18, 2008 (sent for review May 15, 2008). We thank A. Patke for discussions and comments on the manuscript, S. Etherton for help with editing the manuscript, M. Kampmann for advice on the yeast experiments, D. King for mass spectrometry analysis, T. Noriega for technical support, and B. Manjasetty and W. Shi for support during data collection. A.H. was supported by a grant from the Leukemia and Lymphoma Society. Author contributions: P.S. and A.H. designed research; P.S., V.N., and A.H. performed research; P.S., V.N., G.B., and A.H. analyzed data; and P.S. and A.H. wrote the paper. The authors declare no conflict of interest. Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 3CZ7). This article contains supporting information online at www.pnas.org/cgi/content/full/0805813105/DCSupplemental.

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August 22, 2023
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