Mutational analysis of the apical region of domain II of the HCV IRES

Kalliampakou, Katerina I.; Psaridi-Linardaki, Loukia; Mavromara, Penelope

doi:10.1016/s0014-5793(01)03300-2

Cited by 27 publications

(37 citation statements)

References 34 publications

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“…The fact that these mutants decrease IRES-driven initiation by z50% are consistent with the interpretation that while removal of all of dII blocks important steps, mutation of just dIIb likely slows or inhibits a different step. Likewise, this effect coincides with previous work showing decreases in translation due to various mutations made to dIIb (Odreman-Macchioli et al 2001;Kalliampakou et al 2002;Otto and Puglisi 2004). The different SHAPE modification patterns observed with these mutants further supports this interpretation (Fig.…”

Section: Filbin and Kieftsupporting

confidence: 92%

HCV IRES domain IIb affects the configuration of coding RNA in the 40S subunit's decoding groove

Filbin¹,

Kieft²

2011

RNA

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Hepatitis C virus (HCV) uses a structured internal ribosome entry site (IRES) RNA to recruit the translation machinery to the viral RNA and begin protein synthesis without the ribosomal scanning process required for canonical translation initiation. Different IRES structural domains are used in this process, which begins with direct binding of the 40S ribosomal subunit to the IRES RNA and involves specific manipulation of the translational machinery. We have found that upon initial 40S subunit binding, the stem-loop domain of the IRES that contains the start codon unwinds and adopts a stable configuration within the subunit's decoding groove. This configuration depends on the sequence and structure of a different stem-loop domain (domain IIb) located far from the start codon in sequence, but spatially proximal in the IRES d 40S complex. Mutation of domain IIb results in misconfiguration of the HCV RNA in the decoding groove that includes changes in the placement of the AUG start codon, and a substantial decrease in the ability of the IRES to initiate translation. Our results show that two distal regions of the IRES are structurally communicating at the initial step of 40S subunit binding and suggest that this is an important step in driving protein synthesis.

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Section: Filbin and Kieftsupporting

confidence: 92%

HCV IRES domain IIb affects the configuration of coding RNA in the 40S subunit's decoding groove

Filbin¹,

Kieft²

2011

RNA

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“…The HCV IRES RNA domain II cross-links to rpS5 (Fukushi et al 2001); this is the HCV IRES domain previously mentioned as contacting the back side of the ''head'' and changing the conformation of the 40S subunit (Spahn et al 2001b). If the conserved sequences within the apical loop of this domain are mutated, the IRES' ability to form the 80S-IRES complex is substantially reduced (Reynolds et al 1996;Odreman-Macchioli et al 2001;Kalliampakou et al 2002;Otto and Puglisi 2004;Locker et al 2007), establishing a correlation between the HCV IRES' interaction with rpS5, 40S subunit conformational change, eIF2 release, and 80S ribosome formation. This indicates that an interaction with rpS5 is potentially necessary for function, raising the possibility that the same is true of the IGR IRESes.…”

Section: Igr Ires Contacts To the 40s Subunitmentioning

confidence: 99%

RNA structure-based ribosome recruitment: Lessons from the Dicistroviridae intergenic region IRESes

Pfingsten

Kieft²

2008

RNA

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In eukaryotes, the canonical process of initiating protein synthesis on an mRNA depends on many large protein factors and the modified nucleotide cap on the 59 end of the mRNA. However, certain RNA sequences can bypass the need for these proteins and cap, using an RNA structure-based mechanism called internal initiation of translation. These RNAs are called internal ribosome entry sites (IRESes), and the cap-independent initiation pathway they support is critical for successful infection by many viruses of medical and economic importance. In this review, we briefly describe and compare mechanistic and structural groups of viral IRES RNAs, focusing on those IRESes that are capable of direct ribosome recruitment using specific RNA structures. We then discuss in greater detail some recent advances in our understanding of the intergenic region IRESes of the Dicistroviridae, which use the most streamlined ribosome-recruitment mechanism yet discovered. By combining these findings with knowledge of canonical translation and the behavior of other IRESes, mechanistic models of this RNA structure-based process are emerging.

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“…The introduction of mutations in this domain can cause a moderate or total loss of translational ability (Kalliampakou et al, 2002;Kim et al, 2003). In this study, three clustering sites (78-104-107) located in base paired region on the stem-loop II gathered numerous changes (35.4%).…”

Section: Discussionmentioning

confidence: 70%

“…The HCV-IRES domain II induces conformational changes on the ribosome which have been implicated in the decoding process (Kalliampakou et al, 2002). The introduction of mutations in this domain can cause a moderate or total loss of translational ability (Kalliampakou et al, 2002;Kim et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Viral load which reflect the ability of HCV to replicate was not affected by these mutations. However, the importance of stem-loop II for IRES function has been discussed controversially and the changes that occurred in the base-paired regions have not been demonstrated as affecting the translational activity of HCV-IRES (Da Rocha Gomes et al, 2004;Honda et al, 1999a;Kalliampakou et al, 2002;Odreman-Macchioli et al, 2001;Reynolds et al, 1996;Rijnbrand et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

IRES complexity before IFN‐alpha treatment and evolution of the viral load at the early stage of treatment in peripheral blood mononuclear cells from chronic hepatitis C patients

Thélu

Leroy

Ramzan

et al. 2007

Journal of Medical Virology

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show abstract

Mutational analysis of the apical region of domain II of the HCV IRES

Cited by 27 publications

References 34 publications

HCV IRES domain IIb affects the configuration of coding RNA in the 40S subunit's decoding groove

HCV IRES domain IIb affects the configuration of coding RNA in the 40S subunit's decoding groove

RNA structure-based ribosome recruitment: Lessons from the Dicistroviridae intergenic region IRESes

IRES complexity before IFN‐alpha treatment and evolution of the viral load at the early stage of treatment in peripheral blood mononuclear cells from chronic hepatitis C patients

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