Mechanism of the AAA plus ATPases pontin and reptin in the biogenesis of H/ACA RNPs
Mechanism of the AAA plus ATPases pontin and reptin in the biogenesis of H/ACA RNPs
复制标题
DOI：
10.1261/rna.034942.112
复制
发表时间：
2012-10-01
期刊：
影响因子：
4.5
通讯作者：
Meier, U. Thomas
中科院分区：
文献类型：
--
作者：
Machado-Pinilla, Rosario;Liger, Dominique;Meier, U. Thomas
AAA+ atp酶桥蛋白和reptin在一系列惊人的细胞过程中起作用，包括染色质重塑、转录调节、DNA损伤修复和大分子复合物的组装，如RNA聚合酶II和小核仁RNPs。然而，所有这些AAA+ atp酶相关活性的分子机制尚不清楚。本研究发现，在H/ACA RNPs（包括端粒酶）的生物发生过程中，装配因子SHQ1将伪尿嘧啶合成酶NAP57/dyskerin像钳子一样牢牢抓住，而桥蛋白和reptin（作为R2TP复合物的组分）则需要将NAP57从SHQ1撬开。值得注意的是，SHQ1捕获的NAP57结构域包含了x -连锁先天性角化异常（X-DC）的大多数突变，这意味着这两种蛋白之间的界面是这种骨髓衰竭综合征的靶标。着眼于H/ACA RNP生物发生的基本第一步，我们的研究结果首次深入了解了桥蛋白和列蛋白在大分子复合物组装中的作用机制。
The AAA+ ATPases pontin and reptin function in a staggering array of cellular processes including chromatin remodeling, transcriptional regulation, DNA damage repair, and assembly of macromolecular complexes, such as RNA polymerase II and small nucleolar (sno) RNPs. However, the molecular mechanism for all of these AAA+ ATPase associated activities is unknown. Here we document that, during the biogenesis of H/ACA RNPs (including telomerase), the assembly factor SHQ1 holds the pseudouridine synthase NAP57/dyskerin in a viselike grip, and that pontin and reptin (as components of the R2TP complex) are required to pry NAP57 from SHQ1. Significantly, the NAP57 domain captured by SHQ1 harbors most mutations underlying X-linked dyskeratosis congenita (X-DC) implicating the interface between the two proteins as a target of this bone marrow failure syndrome. Homing in on the essential first steps of H/ACA RNP biogenesis, our findings provide the first insight into the mechanism of action of pontin and reptin in the assembly of macromolecular complexes.