Work

Molecular basis of ApoER2-mediated Semliki Forest virus entry

Year: 2025

Type: article

Abstract: The very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) serve as entry receptors for the Semliki Forest virus (SFV). VLDLR interacts with the SFV E1 domain III (DIII) through multiple LDLR class A (LA) domains. However, the ApoER2-mediated SFV entry mechanism remains unclear. Here, we perform biochemical and cellular results and determine the cryogenic electron microscopy (cryo-EM) structures of SFV complexed with ApoER2 LA5 and full-length ApoER2, demonstrating that among the seven LA domains of ApoER2 isoform 1, only LA5 specifically binds to the SFV E1-DIII via a limited interface (353 Å²) and facilitates cell attachment and entry. Site-directed mutagenesis confirms the significance of the residues at the SFV-ApoER2 interface. Significantly, a soluble LA5 decoy receptor neutralizes SFV infection and protects mice from lethal SFV challenge. These findings reveal a LA5-dependent receptor engagement mechanism for SFV entry via ApoER2, distinct from VLDLR. Apolipoprotein E receptor 2 (ApoER2) serves as an entry receptor for Semliki Forest virus (SFV), but the ApoER2-mediated SFV entry mechanism remains unclear. Here, using cryo-EM and complementary approaches, the authors unveil a distinct LA5-dependent binding mode.

Source: Nature Communications

DOI: 10.1038/s41467-025-67550-6