title: Competitive Inhibition of Lysine Acetyltransferase 2B by a Small Motif of the Adenoviral Oncoprotein E1A.
abstract: The adenovirus early region 1A (E1A) oncoprotein hijacks host cells via direct interactions with many key cellular proteins, such as KAT2B, also known as PCAF (p300/CBP associated factor). E1A binds the histone acetyltransferase (HAT) domain of KAT2B to repress its transcriptional activation. However, the molecular mechanism by which E1A inhibits the HAT activity is not known. Here we demonstrate that a short and relatively conserved N-terminal motif (cNM) in the intrinsically disordered E1A protein is crucial for KAT2B interaction, and inhibits its HAT activity through a direct competition with acetyl-CoA, but not its substrate histone H3. Molecular modeling together with a series of mutagenesis experiments suggests that the major helix of E1A cNM binds to a surface of the acetyl-CoA pocket of the KAT2B HAT domain. Moreover, transient expression of the cNM peptide is sufficient to inhibit KAT2B-specific H3 acetylation H3K14ac in vivo Together, our data define an essential motif cNM in N-terminal E1A as an acetyl-CoA entry blocker that directly associates with the entrance of acetyl-CoA binding pocket to block the HAT domain access to its cofactor.
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Shi
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China.
authors.forename: Yanheng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China.
authors.forename: Shijun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China.
authors.forename: Juanyu
authors.initials: J
authors.lastname: Lin
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China.
authors.forename: Chenfang
authors.initials: C
authors.lastname: Gong
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China.
authors.forename: Quanwen
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Goodman Cancer Centre, McGill University, and Department of Medicine, McGill University Health Center, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Xiang-Jiao
authors.initials: XJ
authors.lastname: Yang
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China. Electronic address: chenrc@xmu.edu.cn.
authors.forename: Ruichuan
authors.initials: R
authors.lastname: Chen
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China. Electronic address: appo@xmu.edu.cn.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Ji
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiang'an, Xiamen 361102, China. Electronic address: ahan@xmu.edu.cn.
authors.forename: Aidong
authors.initials: A
authors.lastname: Han
mesh_terms: D000107:Acetylation; D017500:Adenovirus E1A Proteins / Q000737:chemistry / Q000502:physiology*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D000070837:Lysine Acetyltransferases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D017386:Sequence Homology, Amino Acid
chemical_list: D017500:Adenovirus E1A Proteins; D000070837:Lysine Acetyltransferases
keywords: acetyl coenzyme A (acetyl-CoA); acetyltransferase; adenovirus; enzyme inhibitor; structural model