Factorless Ribosome Assembly on the Internal Ribosome Entry Site of Cricket Paralysis Virus

Jan, Eric; Sarnow, Peter

doi:10.1016/s0022-2836(02)01099-9

Cited by 240 publications

(375 citation statements)

References 23 publications

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“…2B). A similar inhibitory effect was observed on CrPV IRES-mediated translation at 10 M pateamine in Krebs extract (data not shown), an IRES with no eIF dependency for 40S ribosome recruitment (33). This inhibitory effect on HCV-driven translation is not observed in vivo (Fig.…”

Section: Discussionsupporting

confidence: 80%

Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation

Bordeleau

Matthews

Wojnar

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

213

245

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RNA helicases are the largest group of enzymes in eukaryotic RNA metabolism. The DEXD͞H-box putative RNA helicases form the helicase superfamily II, whose members are defined by seven highly conserved amino acid motifs, making specific targeting of selected members a challenging pharmacological problem. The translation initiation factor eIF4A is the prototypical DEAD-box RNA helicase that works in conjunction with eIF4B and eIF4H and as a subunit of eIF4F to prepare the mRNA template for ribosome binding, possibly by unwinding the secondary structure proximal to the 5 m 7 GpppN cap structure. We report the identification and characterization of a small molecule inhibitor of eukaryotic translation initiation that acts in an unusual manner by stimulating eIF4A-associated activities. Our results suggest that proper control of eIF4A helicase activity is necessary for efficient ribosome binding and demonstrate the feasibility of selectively targeting DEADbox RNA helicases with small molecules.chemical biology ͉ DEAD-box helicase ͉ pateamine T he ribosome recruitment step of translation initiation is ratelimiting and an important regulatory point whereby cellular environmental cues (e.g., amino acid starvation, mitogenic stimulation, and hypoxia) are linked to the process of translation (1). Two distinct pathways exist for recruitment of the ribosome to the mRNA template. One mechanism is cap-dependent and is facilitated by the presence of the 5Ј cap structure (m 7 GpppN, where N is any nucleotide) on the mRNA. It is catalyzed by the eIF4 class of translation initiation factors and involves the recruitment of ribosomes near the 5Ј end of the mRNA template (1). The second mode involves ribosome recruitment in a cap-independent fashion to an internal ribosome entry site (IRES). Initiation factor requirement for internal ribosome binding varies among IRESes, with some not requiring any factors (2).Preparation of the mRNA template for cap-dependent ribosome recruitment is achieved by eIF4F, eIF4A, eIF4B, eIF4H, and ATP hydrolysis (1). The eIF4F complex is comprised of three subunits: (i) eIF4E, which binds the mRNA cap structure in an ATP-independent fashion; (ii) eIF4A, an RNA helicase that exhibits RNA-dependent ATPase activity and ATPstimulated RNA binding activity (3); and (iii) eIF4G, a modular scaffold that mediates mRNA binding of the 43S preinitiation complex through interactions with eIF3. eIF4B, and eIF4H cooperate with eIF4A to make its helicase activity more processive (4, 5). eIF4A exists as a free form (referred to herein as eIF4A f ) and as a subunit of eIF4F (eIF4A c ) and is thought to cycle through the eIF4F complex during initiation (6-8). When localized in the eIF4F complex, eIF4A c is Ϸ20-fold more efficient as an RNA helicase than when found alone (4, 9), leading to the proposal that eIF4A c is the functional helicase for translation initiation (10). The helicase activity of eIF4F (via eIF4A c ) is thought to unwind local secondary structure in the 5Ј UTR of mRNAs to facilitate cap-dependent ribosome...

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Section: Discussionsupporting

confidence: 80%

Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation

Bordeleau

Matthews

Wojnar

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

213

245

View full text Add to dashboard Cite

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“…On the other hand, structural studies performed on the HCV IRES and the IGR of members of the family Dicistroviridae have shown the capacity of these IRES elements to be accommodated in the interface of the ribosomal subunits (Spahn et al, 2001;Boehringer et al, 2005;Schuler et al, 2006;Pfingsten et al, 2006). Although the IGR and the HCV IRES elements exhibit different structural organization (Kieft et al, 2002;Rijnbrand et al, 2004;Jan & Sarnow, 2002;Nishiyama et al, 2003) and their binding sites in the ribosomal subunit are different, similar conformational changes are induced in the 40S ribosomal subunit (Spahn et al, 2004). This finding opens the possibility that IRES elements could share the property of having a universal structural IRES motif (USIM) that could mediate its direct interaction with the 40S subunit.…”

Section: Relevance Of Rna Structure For Ires Functionmentioning

confidence: 99%

New insights into internal ribosome entry site elements relevant for viral gene expression

Martínez‐Salas

Pacheco

Serrano

et al. 2008

Journal of General Virology

119

106

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A distinctive feature of positive-strand RNA viruses is the presence of high-order structural elements at the untranslated regions (UTR) of the genome that are essential for viral RNA replication. The RNA of all members of the family Picornaviridae initiate translation internally, via an internal ribosome entry site (IRES) element present in the 59 UTR. IRES elements consist of cis-acting RNA structures that usually require specific RNA-binding proteins for translational machinery recruitment. This specialized mechanism of translation initiation is shared with other viral RNAs, e.g. from hepatitis C virus and pestivirus, and represents an alternative to the cap-dependent mechanism. In cells infected with many picornaviruses, proteolysis or changes in phosphorylation of key host factors induces shut off of cellular protein synthesis. This event occurs simultaneously with the synthesis of viral gene products since IRES activity is resistant to the modifications of the host factors. Viral gene expression and RNA replication in positive-strand viruses is further stimulated by viral RNA circularization, involving direct RNA-RNA contacts between the 59 and 39 ends as well as RNA-binding protein bridges. In this review, we discuss novel insights into the mechanisms that control picornavirus gene expression and compare them to those operating in other positive-strand RNA viruses.

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“…1A) (5,6). IGR IRES RNAs bind directly to host cell ribosomes, initiate translation of the downstream message using a non-AUG codon, and induce translocation before a peptide bond is made (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Thus, the IGR IRESs are direct manipulators of the translation machinery, and they show how an RNA can drive its own translation using direct ribosome recruitment without protein intermediaries, reminiscent of an RNA world.…”

mentioning

confidence: 99%

Crystal structures of complexes containing domains from two viral internal ribosome entry site (IRES) RNAs bound to the 70S ribosome

Zhu

Коростелев²,

Costantino³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Internal ribosome entry site (IRES) RNAs are elements of viral or cellular mRNAs that bypass steps of canonical eukaryotic capdependent translation initiation. Understanding of the structural basis of IRES mechanisms is limited, partially due to a lack of highresolution structures of IRES RNAs bound to their cellular targets. Prompted by the universal phylogenetic conservation of the ribosomal P site, we solved the crystal structures of proposed P site binding domains from two intergenic region IRES RNAs bound to bacterial 70S ribosomes. The structures show that these IRES domains nearly perfectly mimic a tRNA•mRNA interaction. However, there are clear differences in the global shape and position of this IRES domain in the intersubunit space compared to those of tRNA, supporting a mechanism for IRES action that invokes hybrid state mimicry to drive a noncanonical mode of translocation. These structures suggest how relatively small structured RNAs can manipulate complex biological machines.ribosome structure | RNA structure | tRNA mimicry

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Factorless Ribosome Assembly on the Internal Ribosome Entry Site of Cricket Paralysis Virus

Cited by 240 publications

References 23 publications

Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation

Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation

New insights into internal ribosome entry site elements relevant for viral gene expression

Crystal structures of complexes containing domains from two viral internal ribosome entry site (IRES) RNAs bound to the 70S ribosome

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