德国马克斯·普朗克多学科科学研究所Vladimir Pena团队揭示人类剪接中催化激活的结构基础。2023年5月10日，《自然》杂志在线发表了这项成果。
研究人员表明，催化激活发生在两个依赖ATP的阶段，由两个螺旋酶驱动：PRP2和Aquarius。Aquarius在剪接中的作用一直是个谜。Aquarius的失活导致剪接体中间物（BAQR复合物）在催化激活过程中发现的停顿。BAQR的冷冻电镜结构揭示了PRP2和Aquarius如何分别重塑Bact和BAQR。值得注意的是，PRP2沿着内含子转位，同时剥离RES复合物，打开SF3B1钳子并解开分支螺旋。通过PPIL4、SKIP和PRP2的氨基末端结构域的组合，转位在分支部位下游6个核苷酸处终止。最后，Aquarius使PRP2以及SF3A和SF3B复合物解离，这促进了分支双链的重新定位来进行催化。这项工作阐明了人类剪接中的催化激活，揭示了DEAH螺旋酶如何运作，并为螺旋酶如何协调其活动提供了一个范例。
据介绍，前体mRNA剪接遵循一个由ATP依赖性RNA螺旋酶驱动的途径。剪接途径的一个关键事件是催化激活，它发生在激活的Bact和具有分支能力的B*剪接体之间的过渡。催化激活是通过螺旋酶PRP2（也称为DHX16）介导的ATP依赖性重塑而发生的。然而，由于PRP2只在剪接体的外围被观察到，它的功能仍然难以理解。
附：英文原文
Title: Structural basis of catalytic activation in human splicing
Author: Schmitzov, Jana, Cretu, Constantin, Dienemann, Christian, Urlaub, Henning, Pena, Vladimir
Issue&Volume: 2023-05-10
Abstract: Pre-mRNA splicing follows a pathway driven by ATP-dependent RNA helicases. A crucial event of the splicing pathway is the catalytic activation, which takes place at the transition between the activated Bact and the branching-competent B* spliceosomes. Catalytic activation occurs through an ATP-dependent remodelling mediated by the helicase PRP2 (also known as DHX16)1,2,3. However, because PRP2 is observed only at the periphery of spliceosomes3,4,5, its function has remained elusive. Here we show that catalytic activation occurs in two ATP-dependent stages driven by two helicases: PRP2 and Aquarius. The role of Aquarius in splicing has been enigmatic6,7. Here the inactivation of Aquarius leads to the stalling of a spliceosome intermediate—the BAQR complex—found halfway through the catalytic activation process. The cryogenic electron microscopy structure of BAQR reveals how PRP2 and Aquarius remodel Bact and BAQR, respectively. Notably, PRP2 translocates along the intron while it strips away the RES complex, opens the SF3B1 clamp and unfastens the branch helix. Translocation terminates six nucleotides downstream of the branch site through an assembly of PPIL4, SKIP and the amino-terminal domain of PRP2. Finally, Aquarius enables the dissociation of PRP2, plus the SF3A and SF3B complexes, which promotes the relocation of the branch duplex for catalysis. This work elucidates catalytic activation in human splicing, reveals how a DEAH helicase operates and provides a paradigm for how helicases can coordinate their activities.
DOI: 10.1038/s41586-023-06049-w
Source: https://www.nature.com/articles/s41586-023-06049-w
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
