Biochemical Basis for LRP1 Interaction With Rift Valley Fever Virus Glycoprotein and Its Role in Viral Entry

The LDL receptor related protein 1 (LRP1) is a host entry factor for Rift Valley fever virus (RVFV), a negative sense RNA virus in the Bunyaviricetes class within the Phenuiviridae family. Previous studies revealed that RVFV glycoproteins (Gn and Gc; GnGc) primarily interact with LRP1 clusters II (CL_II) and IV (CL_IV) to promote viral entry. However, the mechanism of RVFV GnGc binding to LRP1 is not fully characterized. In this study, we have successfully mapped the roles of individual LRP1 ligand binding regions, known as CR domains, and identified CR₂₅ to be sufficient for high affinity RVFV GnGc binding. Analysis of LRP1 multi-CR binding to RVFV GnGc also revealed redundant modes of binding for LRP1. Mutation of a key aromatic residue within CR₂₅ resulted in near complete loss of binding to RVFV GnGc, suggesting a critical role for CR₂₅ in binding to GnGc in vitro. We further assessed the capacity of these CR domains to inhibit RVFV-MP12^GFP infection and determined that more than two contiguous LRP1 CR domains are necessary for in vitro neutralization. Together, these results provide a biochemical basis for LRP1 binding with RVFV GnGc and suggest that a similar mechanism may be at play in LRP1-mediated infection by emerging and re-emerging viruses, including bunyaviruses, alphaviruses, and flaviviruses. These results also highlight that truncated LRP1 ectodomains can be used for immunogen design and therapeutic targeting.