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研究揭示人类17S U2小核糖核蛋白的分子结构
2020-06-04 14:42

德国马普生物物理化学研究所的Holger Stark和Reinhard Lührmann研究组近日取得一项新成果。他们揭示了人类17S U2小核糖核蛋白(snRNP)的分子结构。这一研究成果于2020年6月3日发表在《自然》杂志上。

他们报告了人类17S U2 snRNP的3D冷冻电镜结构,其核心分辨率为4.1Å,并将其与蛋白质交联数据结合起来以确定此snRNP的分子结构。他们的结构表明HEAT结构域(SF3B1HEAT)与PRP5和TAT-SF1相互作用,并在U2 snRNP中保持其开放构象,并且U2 snRNA形成夹在PRP5、TAT-SF1和SF3B1HEAT之间的分支点相互作用的茎环(BSL)。因此,必须发生BSL的实质性重塑和BSL相互作用蛋白的置换,才能形成U2分支位螺旋。

他们的研究提供了一个结构性的解释,来说明为什么在将U2稳定添加至剪接体之前必须先将TAT-SF1置换,并确定PRP5促进U2与分支部位之间稳定相互作用所需的RNP重排。

据悉,snRNP在选择前体mRNA分支位点腺苷(剪接第一步的亲核试剂)中起着至关重要的作用。在早期剪接体形成过程中,稳定添加U2需要DEAD-box ATPase PRP5。最初与分支位点形成碱基对的酵母U2 snRNA核苷酸被螯合在与BSL中,但是人类U2 snRNA是否以类似方式折叠是未知的。U2 SF3B1蛋白是造血系统癌症中常见的突变靶标,它包含一个SF3B1HEAT,在分离的SF3b中具有一个开放的构象,但在剪接体中具有一个封闭的构象,这是U2与分支位点之间稳定相互作用所必需的。

附:英文原文

Author: Zhenwei Zhang, Cindy L. Will, Karl Bertram, Olexandr Dybkov, Klaus Hartmuth, Dmitry E. Agafonov, Romina Hofele, Henning Urlaub, Berthold Kastner, Reinhard Lhrmann, Holger Stark

Issue&Volume: 2020-06-03

Abstract: The U2 small nuclear ribonucleoprotein (snRNP) has an essential role in the selection of the precursor mRNA branch-site adenosine, the nucleophile for the first step of splicing1. Stable addition of U2 during early spliceosome formation requires the DEAD-box ATPase PRP52,3,4,5,6,7. Yeast U2 small nuclear RNA (snRNA) nucleotides that form base pairs with the branch site are initially sequestered in a branchpoint-interacting stem–loop (BSL)8, but whether the human U2 snRNA folds in a similar manner is unknown. The U2 SF3B1 protein, a common mutational target in haematopoietic cancers9, contains a HEAT domain (SF3B1HEAT) with an open conformation in isolated SF3b10, but a closed conformation in spliceosomes11, which is required for stable interaction between U2 and the branch site. Here we report a 3D cryo-electron microscopy structure of the human 17S U2 snRNP at a core resolution of 4.1 and combine it with protein crosslinking data to determine the molecular architecture of this snRNP. Our structure reveals that SF3B1HEAT interacts with PRP5 and TAT-SF1, and maintains its open conformation in U2 snRNP, and that U2 snRNA forms a BSL that is sandwiched between PRP5, TAT-SF1 and SF3B1HEAT. Thus, substantial remodelling of the BSL and displacement of BSL-interacting proteins must occur to allow formation of the U2–branch-site helix. Our studies provide a structural explanation of why TAT-SF1 must be displaced before the stable addition of U2 to the spliceosome, and identify RNP rearrangements facilitated by PRP5 that are required for stable interaction between U2 and the branch site.

DOI: 10.1038/s41586-020-2344-3

Source: https://www.nature.com/articles/s41586-020-2344-3

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
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

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