Ribosomal Chamber Music: Toward an Understanding of IRES Mechanisms

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 42; no. 8; pp. 655 - 668
• Main Authors: Yamamoto, Hiroshi, Unbehaun, Anett, Spahn, Christian M.T.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2017
• Subjects: 5' Untranslated Regions - genetics; eukaryotic translation initiation; internal ribosome entry site; Internal Ribosome Entry Sites - genetics; Nucleic Acid Conformation; ribosome; Ribosomes - chemistry; Ribosomes - genetics; Ribosomes - metabolism; ribosome; internal ribosome entry site; eukaryotic translation initiation
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2017.06.002

Internal initiation is a 5′-end-independent mode of translation initiation engaged by many virus- and putatively some cell-encoded templates. Internal initiation is facilitated by specific RNA tertiary folds, called internal ribosomal entry sites (IRESs), in the 5′ untranslated region (UTR) of the respective transcripts. In this review we discuss recent structural insight into how established IRESs first capture and then manipulate the eukaryotic translation machinery through non-canonical interactions and by guiding the intrinsic conformational flexibility of the eukaryotic ribosome. Because IRESs operate with reduced complexity and constitute minimal systems of initiation, comparison with canonical initiation may allow common mechanistic principles of the ribosome to be delineated. IRESs are cis-acting RNA elements that enable the assembly of elongation competent ribosomes in a cap- and end-independent manner. Their structural diversity is reflected by a varying requirement of initiation factors and distinct modus operandi. IRES-driven translation initiation is established for many positive strand RNA virus families. These IRESs have been subjected to extensive biochemical studies. IRES-mediated protein synthesis has also been claimed for some cellular mRNAs, but further experiments will be necessary to sustain and proof this interesting question. Established viral IRESs operate by structural and functional modularity. Recent high resolution structures and biochemical experiments show us how hepatitis C virus-like and type IV intergenic region IRESs become actively engaged to recruit ribosomes and to govern downstream initiation events. Similarly to eukaryotic translation initiation factors, IRES RNAs tune the conformational energy landscape of the ribosome; for example, to induce opening of the mRNA entry channel by rearrangements of the ribosomal 40S subunit head.