生物谷综合：细胞内绝大多数的RNA分子参与了蛋白质的合成，但有一部分小片段的RNA分子——microRNAs（miRNAs），却对基因的表达起着重要的调控作用。最近，来自宾夕法尼亚大学医学院的研究者发现，miRNAs可以与调节性蛋白“联手”，共同抑制蛋白的表达。研究成果刊登在了最新的Cell期刊上。
据科学家预测，miRNAs可能调控着人类的三分之一左右基因的活性，而且之前的研究还表明，miRNAs的异常活性与癌症及其他疾病有密切联系。
尽管科学家已经知道，哺乳动物中的大多数miRNAs参与抑制RNA的翻译成为蛋白质的过程，但是这过程中的分子机制至今尚不清楚。通过研究人类的miRNAs与调节蛋白Argonaute2（Ago2）的关系，医学副教授Marianthi Kiriakidou（此项研究的通讯作者）与同事一道揭开了miRNAs调控蛋白表达的秘密。
在抑制蛋白合成之前，miRNAs与Argonaute（Ago）家族的蛋白会相互联系。Kiriakidou介绍说，“从与miRNAs的作用形式上看，Ago蛋白处在miRNA的调节通路的枢纽位置上。”
miRNA与Ago间的相互作用，刻画着miRNA调控基因表达的方式。在人类的Ago蛋白家族中，有四种蛋白。Kiriakidou和同事将研究焦点集中在了miRNA与Ago2的相互联系上。Ago2获此殊荣并非没有缘故的，因为它是唯一一种介导RNA干涉（可以抑制基因表达）的Ago蛋白。
原始出处:
Cell, Vol 129, 1141-1151, 15 June 2007
Article
An mRNA m7G Cap Binding-like Motif within Human Ago2 Represses Translation
Marianthi Kiriakidou,1, Grace S. Tan,1 Styliani Lamprinaki,2,3 Mariangels De Planell-Saguer,2 Peter T. Nelson,2,4 and Zissimos Mourelatos2,
1 Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
2 Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Corresponding author
Marianthi Kiriakidou
kiriakim@uphs.upenn.edu
Corresponding author
Zissimos Mourelatos
mourelaz@uphs.upenn.edu
microRNAs (miRNAs) bind to Argonaute (Ago) proteins and inhibit translation or promote degradation of mRNA targets. Human let-7 miRNA inhibits translation initiation of mRNA targets in an m7G cap-dependent manner and also appears to block protein production, but the molecular mechanism(s) involved is unknown and the role of Ago proteins in translational regulation remains elusive. Here we identify a motif (MC) within the Mid domain of Ago proteins, which bears significant similarity to the m7G cap-binding domain of eIF4E, an essential translation initiation factor. We identify conserved aromatic residues within the MC motif of human Ago2 that are required for binding to the m7G cap and for translational repression but do not affect the assembly of Ago2 with miRNA or its catalytic activity. We propose that Ago2 represses the initiation of mRNA translation by binding to the m7G cap of mRNA targets, thus likely precluding the recruitment of eIF4E.
