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.

中文翻译：

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KAT2A 与 α-KGDH 复合物作为组蛋白 H3 琥珀酰转移酶

组蛋白修饰，例如频繁发生的赖氨酸琥珀酰化，是基于染色质过程调节的核心。然而，组蛋白琥珀酰化的机制和功能后果尚不清楚。在这里，我们展示了 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，并与基因启动子区域的赖氨酸乙酰转移酶 2A（KAT2A，也称为 GCN5）结合。我们表明琥珀酰辅酶 A（琥珀酰辅酶 A）与 KAT2A 结合。KAT2A 催化结构域与琥珀酰辅酶 A 复合物在 2.3 Å 分辨率下的晶体结构表明，琥珀酰辅酶 A 与 KAT2A 的深裂口结合，琥珀酰部分指向柔性环 3 的末端，该环采用不同的结构构象以琥珀酰辅酶A结合和乙酰辅酶A结合形式。定点诱变表明该环中的酪氨酸 645 在琥珀酰辅酶 A 与乙酰辅酶 A 的选择性结合中具有重要作用。KAT2A 充当琥珀酰转移酶并琥珀酰化赖氨酸 79 上的组蛋白 H3，最大频率位于基因转录起始位点附近。阻止 α-KGDH 复合物进入细胞核或表达 KAT2A(Tyr645Ala)，可降低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 复合物局部产生琥珀酰辅酶 A 与 KAT2A 的琥珀酰转移酶活性相结合，有助于组蛋白琥珀酰化、肿瘤细胞增殖和肿瘤发展。