Dynamics of IRES-mediated translation

Abstract

One contribution of 12 to a theme issue 'Perspectives on the ribosome'. Viral internal ribosome entry sites (IRESs) are unique RNA elements, which use stable and dynamic RNA structures to recruit ribosomes and drive protein synthesis. IRESs overcome the high complexity of the canonical eukaryotic translation initiation pathway, often functioning with a limited set of eukaryotic initiation factors. The simplest types of IRESs are typified by the cricket paralysis virus intergenic region (CrPV IGR) and hepatitis C virus (HCV) IRESs, both of which independently form high-affinity complexes with the small (40S) ribosomal subunit and bypass the molecular processes of cap-binding and scanning. Owing to their simplicity and ribosomal affinity, the CrPV and HCV IRES have been important models for structural and functional studies of the eukaryotic ribosome during initiation, serving as excellent targets for recent technological breakthroughs in cryogenic electron microscopy (cryo-EM) and single-molecule analysis. High-resolution structural models of ribosome : IRES complexes, coupled with dynamics studies, have clarified decades of biochemical research and provided an outline of the conformational and compositional trajectory of the ribosome during initiation. Here we review recent progress in the study of HCV-and CrPV-type IRESs, highlighting important structural and dynamics insights and the synergy between cryo-EM and single-molecule studies.This article is part of the themed issue 'Perspectives on the ribosome'.

RACK1 on and off the ribosome

“…It is proximal to the mRNA entry and exit channels ( Fig. 2a), and adjacent to the region bound by the HCV IRES, which directly binds the 40S subunit with high-affinity (Johnson et al 2017). The N-and C-termini of RACK1 are in close proximity and surface accessible, so the C-terminal ybbR-tag on RACK1 should be accessible to SFP synthase (Yin et al 2006) on the mature 40S ribosomal subunit (Fig.…”

Location specific small RNA annealing to the HCV 5’ UTR promotes Hepatitis C Virus replication by favoring IRES formation and stimulating virus translation

“…The 5’UTR is a structured RNA that forms 4 stem loops (SL), SLI, SLII, SLIII and SLIV. SLII, SLIII and SLIV comprise the internal ribosomal entry site (IRES) that drives cap-independent HCV translation (Figure 1A) (5, 6). SLII is divided into two parts, SLIIa which induces SLII to form a bent structure that directs SLIIb, to the ribosomal E-site in the head region of the 40S subunit, facilitating 80S ribosome assembly (7–9).…”

The Israeli Acute Paralysis Virus IRES captures host ribosomes by mimicking a ribosomal state with hybrid tRNAs

“…These IRESs are able to induce an artificial state on the ribosome, mimicking a pre-translocation state with tRNAs. Elongation factors eEF2 and eEF1A can then be recruited to effectively bypass the highly regulated initiation [24, 25, 26], jumpstarting directly in the elongation phase [27].…”