LRP1 Interacts with the Rift Valley Fever Virus Glycoprotein Gn via a Calcium-Dependent Multivalent Electrostatic...

Area of Science:

• Virology
• Molecular Biology
• Structural Biology

Background:

• Rift Valley fever virus (RVFV) is a significant zoonotic threat with no available vaccines or antivirals.
• Understanding RVFV entry mechanisms is crucial for developing effective countermeasures.
• The RVFV envelope glycoprotein Gn and its receptor LRP1 are key players in viral entry.

Purpose of the Study:

• To elucidate the molecular basis of RVFV glycoprotein Gn recognition by its receptor, low-density lipoprotein receptor-related protein 1 (LRP1).
• To provide a structural framework for the rational design of vaccines and antiviral therapeutics against RVFV.

Main Methods:

• Bio-layer interferometry (BLI) was used to assess the binding affinity between Gn and LRP1.
• Structural modeling with AlphaFold 3 predicted the interaction interface.
• Site-directed mutagenesis was employed to confirm the role of specific residues and interactions.

Main Results:

• Full-length LRP1 directly binds the Gn head domain with nanomolar affinity in a Ca2+-dependent manner.
• LRP1 clusters II and IV independently interact with Gn, with CL IV showing higher affinity, suggesting multivalent recognition.
• Structural modeling and mutagenesis confirmed Ca2+-stabilized electrostatic interactions between Gn and LRP1, particularly involving acidic residues in LRP1 CL IV.

Conclusions:

• RVFV Gn recognition by LRP1 is driven by a Ca2+-stabilized, electrostatically driven mechanism.
• This detailed molecular understanding provides insights into viral entry and a basis for developing novel antiviral strategies and vaccines.