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

## TL;DR

This study reveals how the Rift Valley fever virus binds to a host cell receptor, offering insights for developing vaccines and treatments.

## Contribution

The paper identifies a calcium-dependent electrostatic mechanism by which the virus's glycoprotein interacts with LRP1.

## Key findings

- LRP1 binds the viral glycoprotein Gn with nanomolar affinity in a calcium-dependent manner.
- Structural modeling shows complementary charges between Gn and LRP1, crucial for binding.
- Mutations in LRP1's acidic residues reduce Gn binding, confirming the role of electrostatic interactions.

## Abstract

The Rift Valley fever virus (RVFV) is a highly pathogenic, mosquito-borne zoonotic virus that poses a significant risk to livestock, human health, and global public health security. Although RVFV is classified by the World Health Organization (WHO) as a priority pathogen with epidemic potential, no licensed vaccines or effective antiviral therapies are currently available. A limited understanding of the molecular mechanisms of RVFV entry has hindered therapeutic development. Here, we elucidate the molecular basis by which the RVFV envelope glycoprotein Gn recognizes its receptor, low-density lipoprotein receptor-related protein 1 (LRP1). Bio-layer interferometry (BLI) demonstrates that full-length LRP1 directly binds the head domain of Gn with nanomolar affinity in a Ca2+-dependent manner. Both LRP1 clusters II (CL II) and IV (CL IV) independently interact with Gn, with CL IV exhibiting stronger affinity, indicating a multivalent recognition mode. Structural modeling using AlphaFold 3 reveals pronounced charge complementarity between basic residues on Gn and acidic, Ca2+-coordinated pockets within LRP1. Mutations in key acidic residues in CL IV greatly reduced Gn binding, confirming the essential roles of Ca2+ coordination and electrostatic interactions. Collectively, our findings define a Ca2+-stabilized, electrostatically driven mechanism for RVFV Gn recognition by LRP1, providing molecular insight into viral entry and a structural framework for the rational design of vaccines and antiviral therapeutics.