Structural insights into Semiliki forest virus receptor binding modes indicate novel mechanism of virus endocytosis
The Very Low-Density Lipoprotein Receptor (VLDLR) is an entry receptor for the prototypic alphavirus Semliki Forest Virus (SFV). However, the precise mechanisms underlying the entry of SFV into cells mediated by VLDLR remain unclear. In this study, we found that of the eight class A (LA) repeats of the VLDLR, only LA2, LA3, and LA5 specifically bind to the native SFV virion while synergistically promoting SFV cell attachment and entry. Furthermore, the multiple cryo-electron microscopy structures of VLDLR-SFV complexes and mutagenesis studies have demonstrated that under physiological conditions, VLDLR primarily binds to E1-DIII of site-1, site-2, and site-1' at the twofold symmetry axes of SFV virion through LA2, LA3, and LA5, respectively. These findings unveil a novel mechanism for viral entry mediated by receptors, suggesting that conformational transitions in VLDLR induced by multivalent binding of LAs facilitate cellular internalization of SFV, with significant implications for the design of antiviral therapeutics.
Authors
- Zhenzhao Sun (ORCID: https://orcid.org/0000-0002-3936-9791)
- Xiangxi Wang (ORCID: https://orcid.org/0000-0003-0635-278X)
- Jingfei Wang (ORCID: https://orcid.org/0000-0003-1035-1069)
- Xijun He (ORCID: https://orcid.org/0000-0002-0427-6405)
- Bingchen Du (ORCID: https://orcid.org/0009-0002-1317-8249)
- Jinyue Wang (ORCID: https://orcid.org/0000-0001-6184-9129)
- Nan Wang (ORCID: https://orcid.org/0000-0002-9936-9179)
- Yutao Chen (ORCID: https://orcid.org/0000-0001-9366-7354)
- Zheng Tao (ORCID: https://orcid.org/0000-0003-0336-6369)
- Shida Wang (ORCID: https://orcid.org/0000-0001-7521-8192)
- Decheng Yang (ORCID: https://orcid.org/0000-0003-1279-7136)
Institutions
- Chinese Academy of Sciences (CN)
- Institute of Biophysics (CN)
- Chinese Academy of Agricultural Sciences (CN)
- University of Chinese Academy of Sciences (CN)
- Harbin Veterinary Research Institute (CN)
Publication Details
- Journal
- PLoS Pathogens
- Published
- 2024-12-20
- DOI
- https://doi.org/10.1371/journal.ppat.1012770
- Citations
- 3
- Primary Topic
- Mosquito-borne diseases and control
- Type
- article
- Field-Weighted Citation Impact
- 1.63
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China
- Agricultural Science and Technology Innovation Program
- Institute of Biophysics, Chinese Academy of Sciences
- Central Public-interest Scientific Institution Basal Research Fund, Chinese Academy of Fishery Sciences