Abstract
As obligatory intracellular parasites, viruses rely on cellular machines to complete their life cycle, and most importantly they recruit the host ribosomes to translate their mRNA. The Hepatitis C viral mRNA initiates translation by directly binding the 40S ribosomal subunit in such a way that the initiation codon is correctly positioned in the P site of the ribosome. Such a property is likely to be central for many viruses, therefore the description of host-pathogen interaction at the molecular level is instrumental to provide new therapeutic targets. In this study, we monitored the 40S ribosomal subunit and the viral RNA structural rearrangement induced upon the formation of the binary complex. We further took advantage of an IRES viral mutant mRNA deficient for translation to identify the interactions necessary to promote translation. Using a combination of structure probing in solution and molecular modeling we establish a whole atom model which appears to be very similar to the one obtained recently by cryoEM. Our model brings new information on the complex, and most importantly reveals some structural rearrangement within the ribosome. This study suggests that the formation of a ‘kissing complex’ between the viral RNA and the 18S ribosomal RNA locks the 40S ribosomal subunit in a conformation proficient for translation.
Highlights
Understanding the host-pathogen interactions is a critical issue for the development of preventive and curative therapies against viruses
In vitro translation assays were performed showing that the chimeric open reading frame (ORF) used does neither interfere with the relative translation efficiency of the WT Hepatitis C Virus (HCV) IRES nor with the phenotype of the mutants
The three guanines in loop IIId have been detected in very early studies as important type III IRES functional determinants [30,32,35]
Summary
Understanding the host-pathogen interactions is a critical issue for the development of preventive and curative therapies against viruses. Of particular interest is the identification of the molecular structures and mechanisms allowing these obligatory intracellular parasites to subvert cellular machines to ensure their replication. Such phenomena provide a unique opportunity to explore physiological and cellular processes at the molecular level. Many viruses have been shown to manipulate translation initiation to further their replication These viral systems provide simplified paradigms that can be used to untangle the functional and structural aspects of this complex process. Translation initiation of some viruses proceeds through a ‘simplified’ mechanism known as internal entry of the ribosome during which the initiation complex is directly recruited on or at the vicinity of the translation start codon [1,3,4,5,6].
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