Structure and nucleic-acid binding of the Drosophila Argonaute 2 PAZ domain
Structure and nucleic-acid binding of the Drosophila Argonaute 2 PAZ domain
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DOI：
10.1038/nature02123
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发表时间：
2003-11-27
期刊：
影响因子：
64.8
通讯作者：
Sattler, M
中科院分区：
文献类型：
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作者：
Lingel, A;Simon, B;Sattler, M
RNA 干扰是一种保守机制，可响应双链 (ds) RNA 的存在来调节基因表达1,2。 RNase III 样酶 Dicer 首先将 dsRNA 切割成 21-23 核苷酸的小干扰 RNA (siR-NA)(3-6)。在效应器步骤中，多聚体 RNA 诱导的沉默复合物 (RISC) 识别与 siRNA 同源的信使 RNA 并促进其降解 (3,7)。 Argonaute 2 蛋白 (Ago2) 是 RISC8,9 的关键组成部分。 Argonaute 和 Dicer 家族蛋白均包含一个功能未知的共同 PAZ 结构域 (10)。在这里，我们展示了果蝇 Ago2 PAZ 结构域的三维核磁共振结构。该结构域采用由保守的疏水残基稳定的核酸结合折叠。核酸结合片位于中心β-桶表面和包含链β3、β4和螺旋α3的保守模块之间的裂口中。由于关键结构残基和结合表面是保守的，我们认为Argonaute和Dicer家族的所有成员中的PAZ结构域都采用具有核酸结合功能的相似折叠，并且这在基因沉默中发挥重要作用。
RNA interference is a conserved mechanism that regulates gene expression in response to the presence of double-stranded (ds) RNAs1,2. The RNase III-like enzyme Dicer first cleaves dsRNA into 21-23-nucleotide small interfering RNAs (siR-NAs)(3-6). In the effector step, the multimeric RNA-induced silencing complex ( RISC) identifies messenger RNAs homologous to the siRNAs and promotes their degradation(3,7). The Argonaute 2 protein (Ago2) is a critical component of RISC8,9. Both Argonaute and Dicer family proteins contain a common PAZ domain whose function is unknown(10). Here we present the three-dimensional nuclear magnetic resonance structure of the Drosophila melanogaster Ago2 PAZ domain. This domain adopts a nucleic-acid-binding fold that is stabilized by conserved hydrophobic residues. The nucleic-acid-binding patch is located in a cleft between the surface of a central beta-barrel and a conserved module comprising strands beta3, beta4 and helix alpha3. Because critical structural residues and the binding surface are conserved, we suggest that PAZ domains in all members of the Argonaute and Dicer families adopt a similar fold with nucleic-acid binding function, and that this plays an important part in gene silencing.