Browsing by Author "Lu, Zhimin"

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    KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase
    (Springer Nature, 2017) Wang, Yugang; Guo, Yusong R.; Liu, Ke; Yin, Zheng; Liu, Rui; Xia, Yan; Tan, Lin; Yang, Peiying; Lee, Jong-Ho; Li, Xin-jian; Hawke, David; Zheng, Yanhua; Qian, Xu; Lyu, Jianxin; He, Jie; Xing, Dongming; Tao, Yizhi Jane; Lu, Zhimin
    Histone modifications, such as the frequently occurring lysine succinylation1,2, are central to the regulation of chromatin-based processes. However, the mechanism and functional consequences of histone succinylation are unknown. Here we show that the α-ketoglutarate dehydrogenase (α-KGDH) complex is localized in the nucleus in human cell lines and binds to lysine acetyltransferase 2A (KAT2A, also known as GCN5) in the promoter regions of genes. We show that succinyl-coenzyme A (succinyl-CoA) binds to KAT2A. The crystal structure of the catalytic domain of KAT2A in complex with succinyl-CoA at 2.3 Å resolution shows that succinyl-CoA binds to a deep cleft of KAT2A with the succinyl moiety pointing towards the end of a flexible loop 3, which adopts different structural conformations in succinyl-CoA-bound and acetyl-CoA-bound forms. Site-directed mutagenesis indicates that tyrosine 645 in this loop has an important role in the selective binding of succinyl-CoA over acetyl-CoA. KAT2A acts as a succinyltransferase and succinylates histone H3 on lysine 79, with a maximum frequency around the transcription start sites of genes. Preventing the α-KGDH complex from entering the nucleus, or expression of KAT2A(Tyr645Ala), reduces gene expression and inhibits tumour cell proliferation and tumour growth. These findings reveal an important mechanism of histone modification and demonstrate that local generation of succinyl-CoA by the nuclear α-KGDH complex coupled with the succinyltransferase activity of KAT2A is instrumental in histone succinylation, tumour cell proliferation, and tumour development.
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    Molecular Basis of KAT2A Selecting Acyl-CoA Cofactors for Histone Modifications
    (AAAS, 2023) Li, Sha; Li, Nan; He, Jie; Zhou, Runxin; Lu, Zhimin; Tao, Yizhi Jane; Guo, Yusong R.; Wang, Yugang
    Emerging discoveries about undocumented acyltransferase activities of known histone acetyltransferases (HATs) advance our understandings in the regulation of histone modifications. However, the molecular basis of HATs selecting acyl coenzyme A (acyl-CoA) substrates for histone modification is less known. We here report that lysine acetyltransferase 2A (KAT2A) as an illustrative instance of HATs can selectively utilize acetyl-CoA, propionyl-CoA, butyryl-CoA, and succinyl-CoA to directly deposit 18 histone acylation hallmarks in nucleosome. By analyzing the co-crystal structures of the catalytic domain of KAT2A in complex with acetyl-CoA, propionyl-CoA, butyryl-CoA, malonyl-CoA, succinyl-CoA, and glutaryl-CoA, we conclude that the alternative substrate-binding pocket of KAT2A and the length and electrostatic features of the acyl chain cooperatively determine the selection of the acyl-CoA substrates by KAT2A. This study reveals the molecular basis underlying the pluripotency of HATs that selectively install acylation hallmarks in nucleosomes, which might serve as instrumental mechanism to precisely regulate histone acylation profiles in cells.
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    Supramolecular assembly of KAT2A with succinyl-CoA for histone succinylation
    (Springer Nature, 2018) Wang, Yugang; Guo, Yusong R.; Xing, Dongming; Tao, Yizhi Jane; Lu, Zhimin