Autoacetylation of the Histone Acetyltransferase Rtt109

Background: TIP60 can be regulated by autoacetylation and deacetylated by SIRT1. Results: Novel lysine residues of TIP60 autoacetylation were identified, and TIP60 can be functionally regulated by HDAC3 through deacetylation. Conclusion: HDAC3 promotes TIP60 ubiquitination and cytoplasmic localization and protects cells from apoptosis after DNA damage. Significance: Our findings provide a better understanding of TIP60 regulatory mechanisms and its cellular functions.

Section: Discussionmentioning

confidence: 99%

Regulation of Histone Acetyltransferase TIP60 Function by Histone Deacetylase 3

Huang

Yang

et al. 2014

“…In a small number of cases the precise contributions of specific, stoichiometric protein acetylation events have been characterized in detail with the authentic post-translational modification. Prior examples include cyclophilin (50), histone modifications (51-53), p53 (54), and acetyltransferase autoacetylation (55)(56)(57). By using expressed protein ligation on SAHH, we establish here, for the first time to our knowledge, the high resolution structural and functional consequences of acetylation at two independent sites in the same protein.…”

Section: Discussionmentioning

confidence: 99%

Regulation of S-Adenosylhomocysteine Hydrolase by Lysine Acetylation

Wang¹,

Kavran²,

Chen³

et al. 2014

“…Briefly, 50 nM hMOF or 200 nM MOZ was incubated with 400 M substrate peptide (H4(1-19) peptide for hMOF and H3 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) for MOZ) (GenScript) and 50 M […”

Section: Methodsmentioning

confidence: 99%

“…PCAF, the MYST family, p300, and Rtt109 are all known to be regulated by lysine autoacetylation, either through chemical or enzymatic means (12)(13)(14)(15)(16)(17)(18)(19). Interestingly, despite the commonality of this automodification among the acetyltransferases, the mechanism of regulation appears to vary between the proteins (20).…”

mentioning

confidence: 99%

“…In the case of p300, several lysine residues within a proteolytically sensitive loop become autoacetylated, leading to a decreased K m for both substrate and cofactor as well as an increased catalytic rate. Autoacetylation of lysine 290 of Rtt109, located about 8 Å away from the enzyme active site, potentiates Rtt109 catalytic activity by decreasing the K m for Ac-CoA and increasing the rate of catalysis (19). Within the MYST family of acetyltransferases, autoacetylation of a conserved active-site lysine residue (Lys-274 in hMOF) has been demonstrated to potentiate enzyme activity (14 -17).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Structural and Functional Role of Acetyltransferase hMOF K274 Autoacetylation

McCullough

Song

Shin

et al. 2016

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 Lys-274 autoacetylation of the human MYST protein Males Absent on the First (hMOF). A mutational scan of hMOF Lys-274 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 a ␣2-␤7 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, which is defective for Lys-274 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 Lys-274 autoacetylation in hMOF stability and cognate substrate acetylation and argues that binding of Ac-CoA to hMOF likely drives Lys-274 autoacetylation for subsequent cognate substrate acetylation.