MYST protein acetyltransferase activity requires active site lysine autoacetylation

Hua Yuan, Dorine Rossetto, Hestia Mellert, Weiwei Dang, Madhusudan Srinivasan, Jamel Johnson, Santosh Hodawadekar, Emily C. Ding, Kaye Speicher, Nebiyu Abshiru, Rocco Perry, Jiang Wu, Chao Yang, Y. George Zheng, David W. Speicher, Pierre Thibault, Alain Verreault, F. Bradley Johnson, Shelley L. Berger, Rolf SternglanzSteven B. McMahon, Jacques Côté, Ronen Marmorstein

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)58-70
Number of pages13
JournalEMBO Journal
Volume31
Issue number1
DOIs
StatePublished - Jan 4 2012
Externally publishedYes

Keywords

  • HATs
  • MYST proteins
  • acetylation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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