Direct functional interaction of initiation factor eIF4G with type 1 internal ribosomal entry sites

Area of Science:

• Molecular Biology
• Virology
• Biochemistry

Background:

• Viral internal ribosomal entry sites (IRESs) enable cap-independent translation initiation.
• Four distinct structural IRES groups exist, with mechanisms for types 2-4 involving interactions with translation factors like eIF4G, 40S ribosomal subunits, and eIF3.
• The initiation mechanism for type 1 IRESs remained largely unknown.

Purpose of the Study:

• To elucidate the mechanism of translation initiation mediated by type 1 viral IRESs.
• To investigate the interaction of type 1 IRESs with translation initiation factors.

Main Methods:

• Investigated the interaction between domain V of type 1 IRESs and eukaryotic initiation factor 4G (eIF4G).
• Assessed the role of eIF4G and eIF4A in recruiting and inducing conformational changes at the 3' borders of type 1 IRESs.
• Correlated the binding ability of mutant type 1 IRESs with eIF4G/eIF4A to their translational activity.

Main Results:

• Domain V of type 1 IRESs specifically interacts with the central domain of eIF4G.
• eIF4G binding to type 1 IRESs promotes the recruitment of eIF4A, leading to conformational changes.
• The interaction of type 1 IRESs with eIF4G and eIF4A is crucial for their translational activity, mirroring type 2 IRES mechanisms.

Conclusions:

• Type 1 IRESs utilize a mechanism involving specific interactions with eIF4G and eIF4A, similar to type 2 IRESs.
• Fundamental aspects of translation initiation mechanisms are conserved between structurally distinct type 1 and type 2 viral IRESs.
• This study reveals conserved molecular interactions underlying cap-independent translation initiation by different viral IRES groups.