Structural basis for VLDLR recognition by eastern equine encephalitis virus

Area of Science:

• Virology
• Structural Biology
• Molecular Interactions

Background:

• Eastern equine encephalitis virus (EEEV) is a highly virulent alphavirus causing severe neurological sequelae in human survivors.
• Alphavirus entry into host cells is mediated by spike glycoproteins (E2 and E1) that bind cellular receptors and facilitate membrane fusion.
• Very-low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) were previously identified as cellular receptors for EEEV and Semliki Forest virus (SFV).

Purpose of the Study:

• To elucidate the structural basis of EEEV and SFV binding to their shared cellular receptor, VLDLR.
• To understand the molecular mechanisms underlying alphavirus-receptor interactions and their evolutionary implications.

Main Methods:

• Single-particle cryo-electron microscopy (cryo-EM) was employed to determine the structures of EEEV and SFV spike glycoproteins complexed with the VLDLR ligand-binding domain.
• Comparative structural analysis of the virus-receptor complexes.

Main Results:

• The cryo-EM structures revealed that EEEV and SFV bind to the VLDLR ligand-binding domain through distinct binding modes.
• Despite divergent binding modes, both viruses utilize the same cellular receptor, VLDLR.

Conclusions:

• The flexible binding modes and small interaction footprints of LDLR-related proteins with viral spike proteins facilitate their adoption as cellular receptors by diverse viruses.
• This adaptability suggests a low evolutionary barrier for alphaviruses to utilize LDLR family members, contributing to their broad host range and emergence potential.