Kiriakidou Marianthi, Tan Grace S, Lamprinaki Styliani, De Planell-Saguer Mariangels, Nelson Peter T, Mourelatos Zissimos
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Cell. 2007 Jun 15;129(6):1141-51. doi: 10.1016/j.cell.2007.05.016. Epub 2007 May 24.
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 m(7)G 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 m(7)G 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 m(7)G 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 m(7)G cap of mRNA targets, thus likely precluding the recruitment of eIF4E.
微小RNA（miRNA）与Argonaute（Ago）蛋白结合，抑制mRNA靶标的翻译或促进其降解。人类let-7 miRNA以m（7）G帽依赖性方式抑制mRNA靶标的翻译起始，并且似乎也会阻断蛋白质生成，但其中涉及的分子机制尚不清楚，Ago蛋白在翻译调控中的作用仍不明确。在此，我们在Ago蛋白的中部结构域中鉴定出一个基序（MC），它与必需的翻译起始因子eIF4E的m（7）G帽结合结构域具有显著相似性。我们在人类Ago2的MC基序中鉴定出保守的芳香族残基，这些残基是与m（7）G帽结合以及翻译抑制所必需的，但不影响Ago2与miRNA的组装或其催化活性。我们提出，Ago2通过与mRNA靶标的m（7）G帽结合来抑制mRNA翻译的起始，从而可能阻止eIF4E的募集。
