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碱基对构象转换调控miR-34a的靶标mRNA Sirt1
2020-05-28 18:18

瑞典卡罗林斯卡医学院Katja Petzold小组在研究中取得进展。他们发现碱基对构象转换调控miR-34a的靶标信使RNA(mRNA) Sirt1 。该项研究成果在线发表在2020年5月27日的《自然》杂志上。

研究人员利用R弛豫-弥散核磁共振和分子模拟揭示了一种基于微小RNA(miRNA)-mRNA双链中单个碱基对重排的动态转换,其将弱的五碱基对种子延长为完整的七碱基对种子。这种转换还导致种子同轴堆叠,并向人Argonaute 蛋白(Ago2)补充螺旋,这类似于原核生物中Ago的活跃状态。这种稳定的瞬时状态会导致对细胞中靶点mRNA的抑制作用增强,从而揭示了这种miRNA–mRNA结构的重要性。

该研究结果与先前关于miRNA逐步靶向过程(从最初的“筛选”状态到“活跃”状态)的发现结合在一起,并揭示了RNA双链体在Ago2中的超出“种子”的作用。

研究人员表示,miRNA调节mRNA的翻译水平。目前,用于解释目标mRNA的选择以及抑制翻译效率的主要参数是miRNA“种子”区域与其对应mRNA之间的碱基配对。

附:英文原文

Title: Base-pair conformational switch modulates miR-34a targeting of Sirt1 mRNA

Author: Lorenzo Baronti, Ileana Guzzetti, Parisa Ebrahimi, Sarah Friebe Sandoz, Emilie Steiner, Judith Schlagnitweit, Bastian Fromm, Luis Silva, Carolina Fontana, Alan A. Chen, Katja Petzold

Issue&Volume: 2020-05-27

Abstract: MicroRNAs (miRNAs) regulate the levels of translation of messenger RNAs (mRNAs). At present, the major parameter that can explain the selection of the target mRNA and the efficiency of translation repression is the base pairing between the ‘seed’ region of the miRNA and its counterpart mRNA1. Here we use R1ρ relaxation-dispersion nuclear magnetic resonance2 and molecular simulations3 to reveal a dynamic switch—based on the rearrangement of a single base pair in the miRNA–mRNA duplex—that elongates a weak five-base-pair seed to a complete seven-base-pair seed. This switch also causes coaxial stacking of the seed and supplementary helix fitting into human Argonaute 2 protein (Ago2), reminiscent of an active state in prokaryotic Ago4,5. Stabilizing this transient state leads to enhanced repression of the target mRNA in cells, revealing the importance of this miRNA–mRNA structure. Our observations tie together previous findings regarding the stepwise miRNA targeting process from an initial ‘screening’ state to an ‘active’ state, and unveil the role of the RNA duplex beyond the seed in Ago2.

DOI: 10.1038/s41586-020-2336-3

Source: https://www.nature.com/articles/s41586-020-2336-3

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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