Identification of Macrodomain Proteins as Novel O-Acetyl-ADP-ribose Deacetylases
Identification of Macrodomain Proteins as Novel O-Acetyl-ADP-ribose Deacetylases
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DOI：
10.1074/jbc.m110.206771
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发表时间：
2011-04-15
影响因子：
4.8
通讯作者：
Ahel, Ivan
中科院分区：
文献类型：
--
作者：
Chen, Dawei;Vollmar, Melanie;Ahel, Ivan
Sirtuins是一个赖氨酸脱乙酰基酶家族，其调节基因沉默、代谢、寿命和染色质结构。Sirtuins利用NAD（+）使蛋白质脱乙酰基，产生O-乙酰基-ADP-核糖（OAADPr）作为反应产物。宏结构域是已知结合ADP-核糖衍生物的普遍存在的蛋白质模块，其通过进化而分化以支持许多不同的蛋白质功能和途径。一些sirtuins和macrodomains作为融合蛋白物理连接或通过相同的操纵子遗传偶联的观察结果提供了一个线索，表明它们的功能可能是相关的。事实上，在这里，我们证明，该产品的sirtuin反应OAADPr是一个基板的几个相关的宏域蛋白：人类MacroD 1，人类MacroD 2，大肠杆菌YmdB，和sirtuin连接MacroD样蛋白从金黄色葡萄球菌。此外，我们表明，来自MacroD缺陷型粗糙脉孢菌菌株的细胞提取物表现出水解OAADPr的能力大幅降低。我们的数据支持一种新的功能的宏域作为OAADPr脱乙酰酶和潜在的在体内的细胞OAADPr的NAD（+）依赖性脱乙酰化产生的调节剂。
Sirtuins are a family of protein lysine deacetylases, which regulate gene silencing, metabolism, life span, and chromatin structure. Sirtuins utilize NAD(+) to deacetylate proteins, yielding O-acetyl-ADP-ribose (OAADPr) as a reaction product. The macrodomain is a ubiquitous protein module known to bind ADP-ribose derivatives, which diverged through evolution to support many different protein functions and pathways. The observation that some sirtuins and macrodomains are physically linked as fusion proteins or genetically coupled through the same operon, provided a clue that their functions might be connected. Indeed, here we demonstrate that the product of the sirtuin reaction OAADPr is a substrate for several related macrodomain proteins: human MacroD1, human MacroD2, Escherichia colt YmdB, and the sirtuin-linked MacroD-like protein from Staphylococcus aureus. In addition, we show that the cell extracts derived from MacroD-deficient Neurospora crassa strain exhibit a major reduction in the ability to hydrolyze OAADPr. Our data support a novel function of macrodomains as OAADPr deacetylases and potential in vivo regulators of cellular OAADPr produced by NAD(+)-dependent deacetylation.