3TO6

Crystal structure of yeast Esa1 HAT domain complexed with H4K16CoA bisubstrate inhibitor

Summary for 3TO6

• Entry DOI: 10.2210/pdb3to6/pdb
• Related: 3TO7 3TO9 3TOA 3TOB
• Descriptor: Histone acetyltransferase ESA1, Histone H4, CARBOXYMETHYL COENZYME *A, ... (4 entities in total)
• Functional Keywords: acetyltransferase, autoacetylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Saccharomyces cerevisiae (Baker's yeast); More
• Cellular location: Nucleus: P02309
• Total number of polymer chains: 2
• Total formula weight: 35305.28

Authors

Yuan, H.,Ding, E.C.,Marmorstein, R. (deposition date: 2011-09-04, release date: 2011-11-09, Last modification date: 2024-10-16)

Primary citation

Yuan, H.,Rossetto, D.,Mellert, H.,Dang, W.,Srinivasan, M.,Johnson, J.,Hodawadekar, S.,Ding, E.C.,Speicher, K.,Abshiru, N.,Perry, R.,Wu, J.,Yang, C.,Zheng, Y.G.,Speicher, D.W.,Thibault, P.,Verreault, A.,Johnson, F.B.,Berger, S.L.,Sternglanz, R.,McMahon, S.B.,Cote, J.,Marmorstein, R.
MYST protein acetyltransferase activity requires active site lysine autoacetylation.
Embo J., 31:58-70, 2011

PubMed 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.

PubMed: 22020126
DOI: 10.1038/emboj.2011.382

Experimental method

X-RAY DIFFRACTION (2.1 Å)