Fungal Rtt109 histone acetyltransferase is an unexpected structural homolog of metazoan p300/CBP

Program in Gene Expression and Regulation, The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Nature Structural & Molecular Biology (Impact Factor: 13.31). 08/2008; 15(7):738-45. DOI: 10.1038/nsmb.1448
Source: PubMed

ABSTRACT 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.

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    • "The p300/ CBP family is restricted to animals. Instead in fungi, there exists a fungal specific structural homolog, Rtt109 (Tang et al., 2008). It is responsible for the acetylation of H3K56 (Schneider et al., 2006), a histone residue at the DNA entry and exit point in the core of a nucleosome (Wang et al., 2008) as opposed to the more accessible N-terminal histone tail residues usually targeted by HATs for transcriptional regulation. "
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    • "3Q66 AcCoA Full length 3Q68 AcCoA Full length [342] Type B Rtt109 Saccharomyces cerevisiae 3QM0 AcCoA HAT [343] "
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    • "However, the mode of autoacetylation in the three HAT families show significant differences. While a single lysine residue within Rtt109 (K290 in yeast Rtt109) is acetylated in a buried site, the lysine residue is located in a helical segment and is about 12 A ˚ from the sulphur atom of Ac-CoA (Lin and Yuan, 2008; Stavropoulos et al, 2008; Tang et al, 2008), nearly twice the distance as the autoacetylated lysine in the MYST proteins. In stark contrast, p300/CBP contains an B60 residue highly basic and proteolytically sensitive loop that harbours multiple lysine acetylation sites (Thompson et al, 2004). "
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    ABSTRACT: The MYST protein lysine acetyltransferases are evolutionarily conserved throughout eukaryotes and acetylate proteins to regulate diverse biological processes including gene regulation, DNA repair, cell-cycle regulation, stem cell homeostasis and development. Here, we demonstrate that MYST protein acetyltransferase activity requires active site lysine autoacetylation. The X-ray crystal structures of yeast Esa1 (yEsa1/KAT5) bound to a bisubstrate H4K16CoA inhibitor and human MOF (hMOF/KAT8/MYST1) reveal that they are autoacetylated at a strictly conserved lysine residue in MYST proteins (yEsa1-K262 and hMOF-K274) in the enzyme active site. The structure of hMOF also shows partial occupancy of K274 in the unacetylated form, revealing that the side chain reorients to a position that engages the catalytic glutamate residue and would block cognate protein substrate binding. Consistent with the structural findings, we present mass spectrometry data and biochemical experiments to demonstrate that this lysine autoacetylation on yEsa1, hMOF and its yeast orthologue, ySas2 (KAT8) occurs in solution and is required for acetylation and protein substrate binding in vitro. We also show that this autoacetylation occurs in vivo and is required for the cellular functions of these MYST proteins. These findings provide an avenue for the autoposttranslational regulation of MYST proteins that is distinct from other acetyltransferases but draws similarities to the phosphoregulation of protein kinases.
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