Functional conservation despite structural divergence in ligand-responsive RNA switches

An internal ribosome entry site (IRES) initiates protein synthesis in RNA viruses, including the hepatitis C virus (HCV). We have discovered ligand-responsive conformational switches in viral IRES elements. Modular RNA motifs of greatly distinct sequence and local secondary structure have been found to serve as functionally conserved switches involved in viral IRES-driven translation and may be captured by identical cognate ligands. The RNA motifs described here constitute a new paradigm for ligand-captured switches that differ from metabolite-sensing riboswitches with regard to their small size, as well as the intrinsic stability and structural definition of the constitutive conformational states. These viral RNA modules represent the simplest form of ligand-responsive mechanical switches in nucleic acids. Significance RNA viruses, including the human pathogenic hepatitis C virus (HCV), use a structured untranslated region of their genome to hijack host cell ribosomes for the synthesis of viral proteins. These genome regions are termed internal ribosome entry site (IRES) elements and are encoded by distinct sequences in different viruses but share common functional RNA motifs. This study shows that viral IRES elements contain conformationally flexible RNA switches, whose state can be captured by the binding of a common ligand. Conformational switching plays a role in the function of the IRES elements. These new RNA switches are smaller than previously discovered “riboswitches” and may be the simplest form of ligand-responsive mechanical modules in nucleic acids.