title: An accurately preorganized IRES RNA structure enables eIF4G capture for initiation of viral translation.
abstract: Many viruses bypass canonical cap-dependent translation in host cells by using internal ribosomal entry sites (IRESs) in their transcripts; IRESs hijack initiation factors for the assembly of initiation complexes. However, it is currently unknown how IRES RNAs recognize initiation factors that have no endogenous RNA binding partners; in a prominent example, the IRES of encephalomyocarditis virus (EMCV) interacts with the HEAT-1 domain of eukaryotic initiation factor 4G (eIF4G). Here we report the solution structure of the J-K region of this IRES and show that its stems are precisely organized to position protein-recognition bulges. This multisite interaction mechanism operates on an all-or-nothing principle in which all domains are required. This preorganization is accomplished by an 'adjuster module': a pentaloop motif that acts as a dual-sided docking station for base-pair receptors. Because subtle changes in the orientation abrogate protein capture, our study highlights how a viral RNA acquires affinity for a target protein.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Imai
authors.affiliation: Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York, USA.
authors.forename: Parimal
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York, USA.
authors.forename: Christopher U T
authors.initials: CU
authors.lastname: Hellen
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: D'Souza
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
mesh_terms: D001665:Binding Sites; D004686:Encephalomyocarditis virus / Q000235:genetics*; D039603:Eukaryotic Initiation Factor-4G / Q000737:chemistry*; D015967:Gene Expression Regulation, Viral; D006801:Humans; D000067556:Internal Ribosome Entry Sites; D055029:Inverted Repeat Sequences; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D014176:Protein Biosynthesis; D021381:Protein Transport; D012333:RNA, Messenger / Q000737:chemistry*; D053838:Scattering, Small Angle; D014961:X-Ray Diffraction
chemical_list: C113920:EIF4G1 protein, human; D039603:Eukaryotic Initiation Factor-4G; D000067556:Internal Ribosome Entry Sites; D012333:RNA, Messenger