title: An mRNA m7G cap binding-like motif within human Ago2 represses translation.
abstract: 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.
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. kiriakim@uphs.upenn.edu
authors.forename: Marianthi
authors.initials: M
authors.lastname: Kiriakidou
authors.forename: Grace S
authors.initials: GS
authors.lastname: Tan
authors.forename: Styliani
authors.initials: S
authors.lastname: Lamprinaki
authors.forename: Mariangels
authors.initials: M
authors.lastname: De Planell-Saguer
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nelson
authors.forename: Zissimos
authors.initials: Z
authors.lastname: Mourelatos
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D060565:Argonaute Proteins; D001483:Base Sequence; D015226:Dinucleoside Phosphates / Q000235:genetics*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics*; D039561:Eukaryotic Initiation Factor-4E / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D008957:Models, Genetic; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D015226:Dinucleoside Phosphates; D015852:Eukaryotic Initiation Factor-2; D039561:Eukaryotic Initiation Factor-4E; D035683:MicroRNAs; D012333:RNA, Messenger; C062229:7-methyl-diguanosine triphosphate