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Nucleic Acids Research Advance Access originally published online on July 13, 2009
Nucleic Acids Research 2009 37(16):5537-5549; doi:10.1093/nar/gkp588
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Nucleic Acids Research, 2009, Vol. 37, No. 16 5537-5549
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

RNA

Conserved functional domains and a novel tertiary interaction near the pseudoknot drive translational activity of hepatitis C virus and hepatitis C virus-like internal ribosome entry sites

Laura E. Easton1, Nicolas Locker2 and Peter J. Lukavsky1,*

1MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 0QH, UK and 2Laboratoire de Cristallographie et RMN Biologiques. Université Paris Descartes. 4 avenue de l'observatoire. 75270 Paris, France

*To whom correspondence should be addressed. Tel: +44 1223 402417; Fax: +44 1223 213556; Email: pjl{at}mrc-lmb.cam.ac.uk

Received April 21, 2009. Revised June 23, 2009. Accepted June 25, 2009.

The translational activity of the hepatitis C virus (HCV) internal ribosome entry site (IRES) and other HCV-like IRES RNAs depends on structured RNA elements in domains II and III, which serve to recruit the ribosomal 40S subunit, eukaryotic initiation factor (eIF) 3 and the ternary eIF2/Met-tRNAiMet/GTP complex and subsequently domain II assists subunit joining. Porcine teschovirus-1 talfan (PTV-1) is a member of the Picornaviridae family, with a predicted HCV-like secondary structure, but only stem-loops IIId and IIIe in the 40S-binding domain display significant sequence conservation with the HCV IRES. Here, we use chemical probing to show that interaction sites with the 40S subunit and eIF3 are conserved between HCV and HCV-like IRESs. In addition, we reveal the functional role of a strictly conserved co-variation between a purine–purine mismatch near the pseudoknot (A–A/G) and the loop sequence of domain IIIe (GAU/CA). These nucleotides are involved in a tertiary interaction, which serves to stabilize the pseudoknot structure and correlates with translational efficiency in both the PTV-1 and HCV IRES. Our data demonstrate conservation of functional domains in HCV and HCV-like IRESs including a more complex structure surrounding the pseudoknot than previously assumed.


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