Structural basis for recognition of 2′,5′-linked oligoadenylates by human ribonuclease L
Structural basis for recognition of 2′,5′-linked oligoadenylates by human ribonuclease L
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DOI：
10.1038/sj.emboj.7600420
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发表时间：
2004-10-13
期刊：
影响因子：
11.4
通讯作者：
Nakamura, KT
中科院分区：
文献类型：
--
作者：
Tanaka, N;Nakanishi, M;Nakamura, KT
干扰素诱导的核糖核酸内切酶，核糖核酸酶L（RNase L），涉及干扰素作用的分子机制和哺乳动物细胞中RNA稳定性的基本控制。RNase L只有在与一种不寻常的激活剂分子结合后才具有催化活性，该激活剂分子在N-末端的一半含有一个50-磷酸化的20，50-连接的寡腺苷酸（2-5A）。在这里，我们报告的N-末端锚蛋白重复结构域（ANK）的人核糖核酸酶L与激活剂2-5A复合的晶体结构。这是锚蛋白重复结构直接与核酸相互作用的第一个结构视图，而不是与蛋白质相互作用。ANK结构域折叠成八个锚蛋白重复元件，并形成具有凹面的延伸弯曲结构。2-5A分子被容纳在凹位点，并直接与锚蛋白重复序列2-4相互作用。有趣的是，在重复序列2和4处发现了两个结构上等同的2-5A结合基序。ANK识别2-5A的结构基础对于设计具有高活化RNase L可能性的稳定2- 5A是必不可少的。
An interferon-induced endoribonuclease, ribonuclease L (RNase L), is implicated in both the molecular mechanism of action of interferon and the fundamental control of RNA stability in mammalian cells. RNase L is catalytically active only after binding to an unusual activator molecule containing a 50-phosphorylated 20,50-linked oligoadenylate (2-5A), in the N-terminal half. Here, we report the crystal structure of the N-terminal ankyrin repeat domain (ANK) of human RNase L complexed with the activator 2-5A. This is the first structural view of an ankyrin repeat structure directly interacting with a nucleic acid, rather than with a protein. The ANK domain folds into eight ankyrin repeat elements and forms an extended curved structure with a concave surface. The 2-5A molecule is accommodated at a concave site and directly interacts with ankyrin repeats 2-4. Interestingly, two structurally equivalent 2-5A binding motifs are found at repeats 2 and 4. The structural basis for 2-5A recognition by ANK is essential for designing stable 2-5As with a high likelihood of activating RNase L.