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Molecular basis of ApoER2-mediated Semliki Forest virus entry.

Du B., Song X., Zhao B., Shi Z., Liu Z., Wang S., Wei L., He X., Huiskonen JT., Yang D., Wang J.

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 Ų) 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.

More information Original publication

DOI

10.1038/s41467-025-67550-6

Type

Journal article

Publication Date

2025-12-01T00:00:00+00:00

Volume

17

Addresses

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Keywords

Animals, Humans, Mice, Semliki forest virus, LDL-Receptor Related Proteins, Receptors, Lipoprotein, Receptors, LDL, Cryoelectron Microscopy, Mutagenesis, Site-Directed, Protein Binding, Virus Internalization, HEK293 Cells, Protein Domains