KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase.
KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase.
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DOI：
10.1038/nature25003
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发表时间：
2017-12-14
期刊：
影响因子：
64.8
通讯作者：
Lu Z
中科院分区：
文献类型：
--
作者：
Wang Y;Guo YR;Liu K;Yin Z;Liu R;Xia Y;Tan L;Yang P;Lee JH;Li XJ;Hawke D;Zheng Y;Qian X;Lyu J;He J;Xing D;Tao YJ;Lu Z
组蛋白修饰，如经常发生的赖氨酸琥珀酰化，是中央的调控染色质为基础的过程。然而，组蛋白琥珀酰化的机制和功能后果是未知的。在这里，我们发现α-酮戊二酸脱氢酶（α-KGDH）复合物位于人类细胞系的细胞核中，并与基因启动子区的赖氨酸乙酰转移酶2A（KAT 2A，也称为GCN 5）结合。我们发现琥珀酰辅酶A（琥珀酰辅酶A）与KAT 2A结合。KAT 2A催化结构域与琥珀酰辅酶A复合物的晶体结构在2.3 μ m分辨率下显示琥珀酰辅酶A与KAT 2A的深裂缝结合，琥珀酰部分指向柔性环3的末端，其在琥珀酰辅酶A结合和乙酰辅酶A结合形式中采用不同的结构构象。定点突变表明，该环中的酪氨酸645在琥珀酰辅酶A相对于乙酰辅酶A的选择性结合中具有重要作用。KAT 2A作为琥珀酰转移酶，将组蛋白H3在赖氨酸79上琥珀酰化，在基因转录起始位点附近频率最高。阻止α-KGDH复合物进入细胞核或KAT 2A（Tyr 645 Ala）的表达，可以减少基因表达并抑制肿瘤细胞增殖和肿瘤生长。这些发现揭示了组蛋白修饰的重要机制，并证明核α-KGDH复合物与KAT 2A的琥珀酰转移酶活性偶联局部产生琥珀酰辅酶A有助于组蛋白琥珀酰化、肿瘤细胞增殖和肿瘤发展。
Histone modifications, such as the frequently occurring lysine succinylation, 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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影响因子：
16
作者：
Clements, A;Poux, AN;Marmorstein, R
通讯作者：
Marmorstein, R
人类GCN5L2抗酰基组歧视的结构基础。
DOI：
10.1107/s2059798316007907
发表时间：
2016-07
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Ringel AE;Wolberger C
通讯作者：
Wolberger C
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
2.9
作者：
Poux, AN;Marmorstein, R
通讯作者：
Marmorstein, R
影响因子：
64.5
作者：
Sutendra, Gopinath;Kinnaird, Adam;Michelakis, Evangelos D.
通讯作者：
Michelakis, Evangelos D.