Hepatitis C virus internal ribosome entry site
| Hepatitis C virus internal ribosome entry site | |
|---|---|
 Predicted secondary structure and sequence conservation of IRES_HCV | |
| Identifiers | |
| Symbol | IRES_HCV |
| Alt. Symbols | HCV_IRES |
| Rfam | RF00061 |
| Other data | |
| RNA type | Cis-reg; IRES |
| Domain(s) | Viruses |
| GO | GO:0043022 |
| SO | SO:0000243 |
| PDB structures | PDBe |
Protein translation of most eukaryotic mRNAs requires association of Met-tRNA, several eukaryotic initiation factors, and GTP with the 40S ribosomal subunit. The ribosome can only bind the capped mRNA after binding to the initiator tRNA. Translation of hepatitis C virus (HCV) mRNA is initiated by a different mechanism from the usual 5' cap-binding model.[1] This alternate mechanism relies on the direct binding of the 40S ribosomal subunit by the internal ribosome entry site (IRES) in the 5' UTR of HCV RNA. HCV IRES adopts a complex structure, and may differ significantly from IRES elements identified in picornaviruses. A small number of eukaryotic mRNA have been shown to be translated by internal ribosome entry.[2][3]
IRES structure
Nucleotides 1-40 of the HCV mRNA are thought not to contribute to translation, and are rather required for genomic RNA replication. The remainder of the HCV 5'-UTR consists of three domains, namely domains II-IV (domain I is located on the 5'-end of the mRNA).
Mechanism of action
HCV IRES binds independently two components of eukaryotic translation initiation machinery, protein eIF3 and 40S small ribosome subunit. Moreover, it binds 40S in such a manner that AUG initiator codon is positioned in ribosomal P-site, thus no ribosomal scanning is required. Consequently scanning factors eIF1 and eIF1A are dispensable for the HCV translation. And so are factors generally required for mRNA binding and unwinding of 5'-UTR, eIF4A, eIF4B and eIF4F. Initiator tRNA is brought then either by eIF2 or, in stress conditions when eIF2 is inactivated, by eIF5B, homologoue of prokaryotic IF2 protein.
References
- ^ Lytle, JR; Wu L; Robertson HD (2002). "Domains on the hepatitis C virus internal ribosome entry site for 40s subunit binding". RNA. 8 (8): 1045–1055. doi:10.1017/S1355838202029965. PMC 1370315. PMID 12212848.
- ^ Beales, LP; Rowlands DJ; Holzenburg A (2001). "The internal ribosome entry site (IRES) of hepatitis C virus visualized by electron microscopy". RNA. 7 (5): 661–670. doi:10.1017/S1355838201001406. PMC 1370118. PMID 11350030.
- ^ Gallego, J; Varani G (2002). "The hepatitis C virus internal ribosome-entry site: a new target for antiviral research". Biochem Soc Trans. 30 (2): 140–145. doi:10.1042/BST0300140. PMID 12023841.
Further reading
- Malygin, A. A.; Kossinova, O. A.; Shatsky, I. N.; Karpova, G. G. (2013). "HCV IRES interacts with the 18S rRNA to activate the 40S ribosome for subsequent steps of translation initiation". Nucleic Acids Research. 41 (18): 8706–8714. doi:10.1093/nar/gkt632. PMC 3794592. PMID 23873958.