Structure of the dual enzyme ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing
Structure of the dual enzyme ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing
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DOI：
10.1016/j.cell.2007.10.057
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发表时间：
2008-01-11
期刊：
影响因子：
64.5
通讯作者：
Sicheri, Frank
中科院分区：
文献类型：
--
作者：
Lee, Kenneth P. K.;Dey, Madhusudan;Sicheri, Frank
Ire 1是一种古老的内质网应激跨膜传感器，具有蛋白激酶和核糖核酸酶双重活性。响应ER应激，Ire 1以剪接体非依赖性方式催化靶mRNA的剪接。我们已经确定了在2.4埃分辨率的Ire 1的双催化区域的晶体结构，揭示了一个域的融合，我们称之为KEN域，蛋白激酶域。激酶结构域的二聚化在执行核糖核酸酶功能的KEN结构域上构成大的催化表面。我们进一步表明，信号诱导的激酶结构域的trans-autophosphorylation允许不受约束的结合的核苷酸，这反过来又促进二聚化组成的核糖核酸酶活性位点。Ire 1的拓扑异构的核糖核酸酶的比较揭示了它们的催化机制的趋同进化。这些发现为理解RNaseL和其他假激酶的作用机制提供了基础，它们占人类激酶组的10%。
Ire1 is an ancient transmembrane sensor of ER stress with dual protein kinase and ribonuclease activities. In response to ER stress, Ire1 catalyzes the splicing of target mRNAs in a spliceosome-independent manner. We have determined the crystal structure of the dual catalytic region of Ire1at 2.4 angstrom resolution, revealing the fusion of a domain, which we term the KEN domain, to the protein kinase domain. Dimerization of the kinase domain composes a large catalytic surface on the KEN domain which carries out ribonuclease function. We further show that signal induced trans-autophosphorylation of the kinase domain permits unfettered binding of nucleotide, which in turn promotes dimerization to compose the ribonuclease active site. Comparison of Ire1 to a topologically disparate ribonuclease reveals the convergent evolution of their catalytic mechanism. These findings provide a basis for understanding the mechanism of action of RNaseL and other pseudokinases, which represent 10% of the human kinome.