Structural basis for VLDLR recognition by eastern equine encephalitis virus

• Published in: Nature communications 2024-08, Vol.15 (1), p.6548-14, Article 6548
• Main Authors: Yang, Pan, Li, Wanyu, Fan, Xiaoyi, Pan, Junhua, Mann, Colin J., Varnum, Haley, Clark, Lars E., Clark, Sarah A., Coscia, Adrian, Basu, Himanish, Smith, Katherine Nabel, Brusic, Vesna, Abraham, Jonathan
• Format: Article
• Language: English
• Subjects: 101/28; 13; 13/31; 14; 14/35; 631/326/596/1282; 631/535/1258/1259; 64; 9/10; Animals; Apolipoprotein E; Binding; Cell fusion; Cell membranes; Cellular structure; Cryoelectron Microscopy; Eastern equine encephalitis; Electron microscopy; Encephalitis; Encephalitis Virus, Eastern Equine - metabolism; Encephalitis Virus, Eastern Equine - ultrastructure; Firing pattern; Glycoproteins; Humanities and Social Sciences; Humans; Intellectual disabilities; Low density lipoprotein; Low density lipoprotein receptors; Models, Molecular; multidisciplinary; Neurological complications; Paralysis; Pest outbreaks; Protein Binding; Proteins; Receptor density; Receptors; Receptors, LDL - chemistry; Receptors, LDL - metabolism; Receptors, Virus - chemistry; Receptors, Virus - metabolism; Science; Science (multidisciplinary); Semliki forest virus - metabolism; Viral Envelope Proteins - chemistry; Viral Envelope Proteins - metabolism; Viral Envelope Proteins - ultrastructure; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50887-9

Eastern equine encephalitis virus (EEEV) is the most virulent alphavirus that infects humans, and many survivors develop neurological sequelae, including paralysis and intellectual disability. Alphavirus spike proteins comprise trimers of heterodimers of glycoproteins E2 and E1 that mediate binding to cellular receptors and fusion of virus and host cell membranes during entry. We recently identified very-low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) as cellular receptors for EEEV and a distantly related alphavirus, Semliki Forest virus (SFV). Here, we use single-particle cryo-electron microscopy (cryo-EM) to determine structures of the EEEV and SFV spike glycoproteins bound to the VLDLR ligand-binding domain and found that EEEV and SFV interact with the same cellular receptor through divergent binding modes. Our studies suggest that the ability of LDLR-related proteins to interact with viral spike proteins through very small footprints with flexible binding modes results in a low evolutionary barrier to the acquisition of LDLR-related proteins as cellular receptors for diverse sets of viruses. Alphaviruses include several important human pathogens with outbreak potential. Here, the authors found that eastern equine encephalitis virus and Semliki Forest virus use distinct surfaces on their spike proteins to bind their shared receptor, VLDLR.