Molecular Basis of KAT2A Selecting Acyl-CoA Cofactors for Histone Modifications.
Molecular Basis of KAT2A Selecting Acyl-CoA Cofactors for Histone Modifications.
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DOI：
10.34133/research.0109
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Li S;Li N;He J;Zhou R;Lu Z;Tao YJ;Guo YR;Wang Y
新发现的已知组蛋白乙酰基转移酶（HAT）的酰基转移酶活性的文件推进了我们的理解，在组蛋白修饰的调控。然而，HAT选择酰基辅酶A（酰基-CoA）底物进行组蛋白修饰的分子基础鲜为人知。本文报道了赖氨酸乙酰转移酶2A（KAT 2A）作为HAT的一个典型例子，可以选择性地利用乙酰辅酶A、丙酰辅酶A、丁酰辅酶A和琥珀酰辅酶A直接存款18个组蛋白酰化标志物。通过分析KAT 2A的催化结构域与乙酰辅酶A、丙酰辅酶A、丁酰辅酶A、丙二酰辅酶A、琥珀酰辅酶A和戊二酰辅酶A复合物的共晶结构，我们得出结论，KAT 2A的替代底物结合口袋以及酰基链的长度和静电特征共同决定了KAT 2A对酰基辅酶A底物的选择。这项研究揭示了HAT多能性的分子基础，HAT选择性地在核小体中安装酰化标记，这可能是精确调节细胞中组蛋白酰化谱的工具机制。
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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