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Structural basis for VLDLR recognition by eastern equine encephalitis virus

Author

Listed:
  • Pan Yang

    (Harvard Medical School)

  • Wanyu Li

    (Harvard Medical School)

  • Xiaoyi Fan

    (Harvard Medical School)

  • Junhua Pan

    (Harvard Medical School
    Hubei University of Technology)

  • Colin J. Mann

    (Harvard Medical School)

  • Haley Varnum

    (Harvard Medical School)

  • Lars E. Clark

    (Harvard Medical School)

  • Sarah A. Clark

    (Harvard Medical School)

  • Adrian Coscia

    (Harvard Medical School)

  • Himanish Basu

    (Harvard Medical School)

  • Katherine Nabel Smith

    (Harvard Medical School)

  • Vesna Brusic

    (Harvard Medical School)

  • Jonathan Abraham

    (Harvard Medical School
    Brigham & Women’s Hospital
    Broad Institute of Harvard and MIT)

Abstract

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.

Suggested Citation

  • Pan Yang & Wanyu Li & Xiaoyi Fan & Junhua Pan & Colin J. Mann & Haley Varnum & Lars E. Clark & Sarah A. Clark & Adrian Coscia & Himanish Basu & Katherine Nabel Smith & Vesna Brusic & Jonathan Abraham, 2024. "Structural basis for VLDLR recognition by eastern equine encephalitis virus," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50887-9
    DOI: 10.1038/s41467-024-50887-9
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