Viral internal ribosome entry site structures segregate into two distinct morphologies

Area of Science:

• Virology
• Molecular Biology
• Structural Biology

Background:

• Many viruses initiate protein synthesis via cap-independent mechanisms using internal ribosome entry sites (IRESs).
• Predicting RNA folding patterns of IRES elements has relied on sequence and biochemical data.
• Biophysical confirmation of IRES structures has been limited, with only the hepatitis C virus (HCV) IRES structure well-characterized.

Purpose of the Study:

• To compare the structures of flavivirus and picornavirus IRES elements using biophysical methods.
• To determine if flavivirus IRESs share structural similarities with the known HCV IRES structure.
• To characterize the morphology of larger picornavirus IRES elements.

Main Methods:

• Negative stain transmission electron microscopy was employed.
• Extensive comparison of multiple flavivirus and picornavirus IRES elements was performed.

Main Results:

• Flavivirus IRESs (GB virus-B, GB virus-C, classical swine fever virus) exhibit structures similar to the HCV IRES.
• An IRES from human herpesvirus 8 mRNA also adopts a similar structure to the HCV IRES.
• Larger picornavirus IRESs (foot-and-mouth disease virus, rhinovirus, encephalomyocarditis virus, hepatitis A virus) show a distinct morphology, featuring a backbone with two stems, differing from flavivirus IRESs.

Conclusions:

• Flavivirus IRESs and the HCV IRES share a conserved, open structural motif.
• Picornavirus IRESs possess a distinct, larger structure compared to flavivirus IRESs.
• These structural differences may reflect distinct mechanisms of viral protein synthesis initiation.