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Publication Abstract from PubMed

Many histone acetyltransferases undergo autoacetylation, either through chemical or enzymatic means, to potentiate enzymatic cognate substrate lysine acetylation, although the mode and molecular role of such autoacetylation is poorly understood. The MYST family of histone acetyltransferases is autoacetylated at an active site lysine residue to facilitate cognate substrate lysine binding and acetylation. Here, we report on a detailed molecular investigation of K274 autoacetylation of the human MYST protein Males Absent on the First (hMOF). A mutational scan of hMOF K274 reveals that all amino acid substitutions of this residue are able to bind cofactor but are significantly destabilized, both in vitro and in cells, and are catalytically inactive for cognate histone H4 peptide lysine acetylation. The X-ray crystal structure of a hMOF K274P mutant suggests that the reduced stability and catalytic activity stems from a disordering of the residue 274-harboring alpha2-beta7 loop. We also provide structural evidence that a C316S/E350Q mutant, which is defective for cognate substrate lysine acetylation; and biochemical evidence that a K268M mutant, that is defective for K274 chemical acetylation in the context of a K274-peptide, can still undergo quantitative K274 autoacetylation. Together, these studies point to the critical and specific role of hMOF K274 autoacetylation in hMOF stability and cognate substrate acetylation and argues that binding of Ac-CoA to hMOF likely drives K274 autoacetylation for subsequent cognate substrate acetylation.

Structural and Functional Role of Acetyltransferase hMOF K274 Autoacetylation.,Mccullough CE, Song S, Shin MH, Johnson FB, Marmorstein R J Biol Chem. 2016 Jul 5. pii: jbc.M116.736264. PMID:27382063^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.