生物谷綜合：細(xì)胞內(nèi)絕大多數(shù)的RNA分子參與了蛋白質(zhì)的合成,，但有一部分小片段的RNA分子——microRNAs（miRNAs）,，卻對(duì)基因的表達(dá)起著重要的調(diào)控作用。最近,，來自賓夕法尼亞大學(xué)醫(yī)學(xué)院的研究者發(fā)現(xiàn),，miRNAs可以與調(diào)節(jié)性蛋白“聯(lián)手”，共同抑制蛋白的表達(dá),。研究成果刊登在了最新的Cell期刊上,。
據(jù)科學(xué)家預(yù)測(cè)，miRNAs可能調(diào)控著人類的三分之一左右基因的活性,，而且之前的研究還表明,，miRNAs的異常活性與癌癥及其他疾病有密切聯(lián)系,。
盡管科學(xué)家已經(jīng)知道,，哺乳動(dòng)物中的大多數(shù)miRNAs參與抑制RNA的翻譯成為蛋白質(zhì)的過程，但是這過程中的分子機(jī)制至今尚不清楚,。通過研究人類的miRNAs與調(diào)節(jié)蛋白Argonaute2（Ago2）的關(guān)系,，醫(yī)學(xué)副教授Marianthi Kiriakidou（此項(xiàng)研究的通訊作者）與同事一道揭開了miRNAs調(diào)控蛋白表達(dá)的秘密。
在抑制蛋白合成之前,，miRNAs與Argonaute（Ago）家族的蛋白會(huì)相互聯(lián)系,。Kiriakidou介紹說，“從與miRNAs的作用形式上看,，Ago蛋白處在miRNA的調(diào)節(jié)通路的樞紐位置上,。”
miRNA與Ago間的相互作用,，刻畫著miRNA調(diào)控基因表達(dá)的方式。在人類的Ago蛋白家族中,，有四種蛋白,。Kiriakidou和同事將研究焦點(diǎn)集中在了miRNA與Ago2的相互聯(lián)系上。Ago2獲此殊榮并非沒有緣故的,，因?yàn)樗俏ㄒ灰环N介導(dǎo)RNA干涉（可以抑制基因表達(dá)）的Ago蛋白,。
原始出處:
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
[email protected]
Corresponding author
Zissimos Mourelatos
[email protected]
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.
