全原子模拟阐明了 U2AF2 癌症相关突变对前体 mRNA 识别的影响,Journal of Chemical Information and Modeling

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全原子模拟阐明了 U2AF2 癌症相关突变对前体 mRNA 识别的影响
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2022-08-30 , DOI: 10.1021/acs.jcim.2c00511
Riccardo Rozza ₁ , Andrea Saltalamacchia ₂ , Clarissa Orrico ₂ , Pavel Janoš ₁ , Alessandra Magistrato ₁

Affiliation

U2AF2 剪接因子由两个串联 RNA 识别基序 (RRM) 组成，通过一个灵活的接头连接，选择早产 mRNA 的内含子多嘧啶序列，从而确保剪接保真度。越来越多的证据表明关键剪接因子（包括 U2AF2）的突变与多种癌症有关。然而，U2AF2 癌症相关突变对多嘧啶识别的影响仍不清楚。在这里，我们结合了 U2AF2 的广泛（18 μs 长）全原子分子动力学模拟和动态网络理论分析 (NWA)，在其野生型和存在六种最常见的癌症相关突变的情况下，必然聚-U链。我们的结果表明，选定的突变会影响两个热点区域的 pre-mRNA 结合，而不管这些突变体位于不同的 U2AF2 域上的位置。作为补充，NWA 追踪了交叉通信通路的存在，将每个突变位点连接到这些识别热点，其强度因突变而改变。我们的结果表明两个 U2AF2 的 RRM 存在结构/动力学相互作用，这是识别多嘧啶束的基础，并表明癌症相关突变通过改变 RRM 的协同作用影响多嘧啶选择。这种机制可能被其他 RNA 结合蛋白共享，如 U2AF2，具有多域结构和高可塑性。我们的结果表明两个 U2AF2 的 RRM 存在结构/动力学相互作用，这是识别多嘧啶束的基础，并表明癌症相关突变通过改变 RRM 的协同作用影响多嘧啶选择。这种机制可能被其他 RNA 结合蛋白共享，如 U2AF2，具有多域结构和高可塑性。我们的结果表明两个 U2AF2 的 RRM 存在结构/动力学相互作用，这是识别多嘧啶束的基础，并表明癌症相关突变通过改变 RRM 的协同作用影响多嘧啶选择。这种机制可能被其他 RNA 结合蛋白共享，如 U2AF2，具有多域结构和高可塑性。

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All-Atom Simulations Elucidate the Impact of U2AF2 Cancer-Associated Mutations on Pre-mRNA Recognition

The U2AF2 splicing factor, made of two tandem RNA recognition motifs (RRMs) joined by a flexible linker, selects the intronic polypyrimidine sequence of premature mRNA, thus ensuring splicing fidelity. Increasing evidence links mutations of key splicing factors, including U2AF2, to a variety of cancers. Nevertheless, the impact of U2AF2 cancer-associated mutations on polypyrimidine recognition remains unclear. Here, we combined extensive (18 μs-long) all-atom molecular dynamics simulations and dynamical network theory analysis (NWA) of U2AF2, in its wild-type form and in the presence of the six most frequent cancer-associated mutations, bound to a poly-U strand. Our results reveal that the selected mutations affect the pre-mRNA binding at two hot spot regions, irrespectively of where these mutants are placed on the distinct U2AF2 domains. Complementarily, NWA traced the existence of cross-communication pathways, connecting each mutation site to these recognition hot spots, whose strength is altered by the mutations. Our outcomes suggest the existence of a structural/dynamical interplay of the two U2AF2’s RRMs underlying the recognition of the polypyrimidine tract and reveal that the cancer-associated mutations affect the polypyrimidine selection by altering the RRMs’ cooperativity. This mechanism may be shared by other RNA binding proteins hallmarked, like U2AF2, by multidomain architecture and high plasticity.

更新日期：2022-08-30

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