Deciphering molecular mechanisms stabilizing the reovirus-binding complex

Area of Science:

• Virology
• Biophysics
• Nanotechnology

Background:

• Mammalian orthoreoviruses (reoviruses) are implicated in celiac disease and possess oncolytic potential for cancer therapy.
• Viral attachment protein σ1 mediates initial reovirus binding to host cells via cell-surface glycans and junctional adhesion molecule-A (JAM-A).
• The conformational dynamics of σ1 during viral attachment and infection remain poorly understood.

Purpose of the Study:

• To investigate how the mechanical properties of the viral capsid protein σ1 influence reovirus binding capacity and infectivity.
• To elucidate the role of conformational changes in σ1 during the multistep process of host cell attachment and infection initiation.

Main Methods:

• Combined biophysical techniques, including single-virus force spectroscopy.
• Molecular biology approaches.
• In silico simulations and computational modeling.

Main Results:

• GM2 enhances σ1 affinity for JAM-A by creating a more stable binding interface.
• Conformational changes in σ1 to an extended, rigid state significantly increase avidity for JAM-A.
• Reduced σ1 flexibility, despite impairing multivalent attachment, enhances viral infectivity, highlighting the importance of fine-tuned conformational dynamics.

Conclusions:

• The nanomechanics of viral attachment proteins, specifically σ1, are critical for initiating viral infection.
• Understanding these mechanical properties provides insights for developing novel antiviral drugs.
• This knowledge can also aid in engineering improved oncolytic viral vectors for cancer therapy.