A tertiary structure model of the internal ribosome entry site (IRES) for methionine-independent initiation of translation

Kanamori, Yasushi; Nakashima, Nobuhiko

doi:10.1017/s1355838201001741

Cited by 123 publications

(145 citation statements)

References 24 publications

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“…Hence, these studies also indicated that SL1 is not required for 80S preinitiation complex formation but that intact SL2 is required. These results are similar to those reported from in vitro studies with RhPV and PSIV (Domier et al, 2000;Kanamori & Nakashima, 2001). From these studies we conclude that the RhPV IG IRES initiated translation with efficiencies comparable to that of the 59 IRES and that the IG IRES was not dependent on the presence of the 59 IRES.…”

supporting

confidence: 91%

“…These results showed that the RhPV IG IRES directed internal initiation in Sf9 cells. In addition, it confirmed the in vitro observations with RhPV and PSIV that showed that the 39 pseudoknot was required for IRES activity (Domier et al, 2000;Kanamori & Nakashima, 2001).…”

supporting

confidence: 82%

“…However, rather than expressing single, large polyproteins with structural proteins located proximal to the amino termini, the RhPV genome contains two large open reading frames (ORFs) that express nonstructural and capsid polyproteins from 59-and 39-proximal ORFs, respectively (Moon et al, 1998). Both ORFs are preceded by internal ribosome entry sites (IRESs) that are structurally and functionally different (Domier et al, 2000;Kanamori & Nakashima, 2001;Wilson et al, 2000b;Woolaway et al, 2001). The RhPV 59 IRES is located upstream of the initiation codon of the first ORF and directs translation initiation at AUG codons in animal, insect and plant cell extracts (Woolaway et al, 2001).…”

mentioning

confidence: 99%

“…Similarly, the IG IRES of PSIV initiates translation at a CUU codon (Sasaki & Nakashima, 1999). Many primary and secondary structural features of the IG IRESs of members of the Dicistroviridae are conserved, including three pseudoknots that are required for activity (Kanamori & Nakashima, 2001). The use of the noncanonical initiation codons is explained by the finding that the CrPV IG IRES initiates translation in a process that does not involve methionyl-tRNA and is independent of translation initiation factor eIF2a (Wilson et al, 2000a).…”

mentioning

confidence: 99%

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In vivo activity of Rhopalosiphum padi virus internal ribosome entry sites

Domier

McCoppin

2003

Journal of General Virology

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supporting

confidence: 91%

supporting

confidence: 82%

mentioning

confidence: 99%

mentioning

confidence: 99%

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In vivo activity of Rhopalosiphum padi virus internal ribosome entry sites

Domier

McCoppin

2003

Journal of General Virology

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“…Molecular structure of the CrPV IRES RNA At the present resolution, it is not possible to derive directly the identity of the helical RNA elements or their directionality, but the established secondary structure of the CrPV IRES [16][17][18] indicates the presence of three pseudoknots (PKI, PKII and PKIII) and establishes the length and connectivity of the helical elements (Fig. 2c).…”

Section: Cryo-em Reconstruction Of the Crpv Ires-80s Complexmentioning

confidence: 94%

Structure of the ribosome-bound cricket paralysis virus IRES RNA

Schüler

Connell

Lescoute

et al. 2006

Nat Struct Mol Biol

182

273

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Internal ribosome entry sites (IRESs) facilitate an alternative, end-independent pathway of translation initiation. A particular family of dicistroviral IRESs can assemble elongation-competent 80S ribosomal complexes in the absence of canonical initiation factors and initiator transfer RNA. We present here a cryo-EM reconstruction of a dicistroviral IRES bound to the 80S ribosome. The resolution of the cryo-EM reconstruction, in the subnanometer range, allowed the molecular structure of the complete IRES in its active, ribosome-bound state to be solved. The structure, harboring three pseudoknot-containing domains, each with a specific functional role, shows how defined elements of the IRES emerge from a compactly folded core and interact with the key ribosomal components that form the A, P and E sites, where tRNAs normally bind. Our results exemplify the molecular strategy for recruitment of an IRES and reveal the dynamic features necessary for internal initiation.Initiation of protein synthesis is an essential phase of protein synthesis and a key regulatory step in gene expression 1,2 . In eukaryotes, the canonical 5¢ cap-dependent pathway is facilitated and orchestrated by approximately 11 translation initiation factors. However, IRES RNAs can functionally substitute for initiation factors and facilitate the alternative pathway of internal initiation 3,4 . IRESs are present in 5¢ untranslated regions (UTRs) of many viral RNAs and are efficient tools to hijack the translational apparatus of the host during viral infection. They are also used by a subset of cellular messenger RNAsfor example, several proto-oncogenes [3][4][5] . In this context, they act as regulatory tools and are used to initiate translation during cellular stress or other periods when overall global translation is compromised.The molecular mechanisms of initiation by IRES RNAs are largely unknown. IRES RNAs fall into different classes that are distinguished by their structure and dependence on different sets of canonical initiation factors and IRES trans-acting factors 3-6 . The simplest mechanism of initiation is used by the intergenic IRESs of dicistroviruses, such as the cricket paralysis virus (CrPV). This family of IRESs does not require any initiation factor or even initiator tRNA in order to assemble elongation-competent 80S ribosomes 7-10 . According to biochemical studies, the IRES binds directly to the ribosomal 40S subunit and sets the translational reading frame by positioning the first codon into the ribosomal A site. This is highly unusual, because canonical initiation starts from the P site. Moreover, like the hepatitis C virus IRES 11 , the CrPV IRES actively manipulates the conformation of the translational machinery, suggesting that the IRES acts like an RNA-based translation factor 12 .A detailed knowledge of the CrPV IRES structure, especially in the ribosome-bound state, is a prerequisite for understanding the mechanism of internal initiation without initiation factors. The low resolution of the previous cryo-EM maps limit...

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Unmasking the information encoded as structural motifs of viral RNA genomes: a potential antiviral target

Romero-López

Berzal‐Herranz

2013

Reviews in Medical Virology

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RNA viruses show enormous capacity to evolve and adapt to new cellular and molecular contexts, a consequence of mutations arising from errors made by viral RNA-dependent RNA polymerase during replication. Sequence variation must occur, however, without compromising functions essential for the completion of the viral cycle. RNA viruses are safeguarded in this respect by their genome carrying conserved information that does not code only for proteins but also for the formation of structurally conserved RNA domains that directly perform these critical functions. Functional RNA domains can interact with other regions of the viral genome and/or proteins to direct viral translation, replication and encapsidation. They are therefore potential targets for novel therapeutic strategies. This review summarises our knowledge of the functional RNA domains of human RNA viruses and examines the achievements made in the design of antiviral compounds that interfere with their folding and therefore their function.

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A tertiary structure model of the internal ribosome entry site (IRES) for methionine-independent initiation of translation

Cited by 123 publications

References 24 publications

In vivo activity of Rhopalosiphum padi virus internal ribosome entry sites

In vivo activity of Rhopalosiphum padi virus internal ribosome entry sites

Structure of the ribosome-bound cricket paralysis virus IRES RNA

Unmasking the information encoded as structural motifs of viral RNA genomes: a potential antiviral target

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