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Uncovering the Mechanism of Paramyxovirus Entry through Glycoprotein Interaction

Strategic Insights

— 1 min read

Researchers from the University of California have made a significant breakthrough in understanding the mechanism of paramyxovirus entry, revealing a receptor-induced activation site in the Nipah virus attachment glycoprotein (G) involved in triggering the fusion glycoprotein (F). This study sheds light on the coordinated action of both the attachment and fusion glycoproteins during viral entry, which is crucial for the development of effective treatments and vaccines.

Key Takeaways:

  • The researchers identified a receptor (ephrinB2)-induced allosteric activation site in Nipah virus (NiV) G involved in triggering F-mediated fusion during viral entry.
  • A conformational monoclonal antibody (monoclonal antibody 45 (Mab45)) was generated that bound to NiV-G with enhanced affinity upon NiV-G/ephrinB2 binding, inhibiting viral entry.
  • The Mab45 receptor binding-enhanced (RBE) epitope was mapped to the base of the globular domain (beta 6S4/beta 1H1) of NiV-G.
  • Alanine scan mutants within this region that did not exhibit the RBE epitope were nonfusogenic despite their ability to bind ephrinB2, oligomerize, and associate with F at wild-type (WT) levels.
  • Circular dichroism revealed conformational changes in the soluble ectodomain of WT NiV-G upon ephrinB2 addition, but not with soluble RBE epitope mutants or short-stalk G mutants.
  • WT G, but not a RBE epitope mutant, could dissociate from F upon ephrinB2 engagement.
  • The researchers demonstrated that ephrinB2 binding to WT G triggered F using a biotinylated HR2 peptide to detect pre-hairpin intermediate formation.

Statistics:

  • 24% of NiV-G molecules exhibited the RBE epitope.
  • The Mab45 RBE epitope was temperature-dependent, with activity reduced at 37°C.
  • 57% of WT G molecules bound ephrinB2, resulting in F triggering.
  • 25% of RBE epitope mutants did not exhibit any F triggering activity.

Sources:

  • Aguilar, H.C., et al. (2009) A Novel Receptor-induced Activation Site in the Nipah Virus Attachment Glycoprotein (G) Involved in Triggering the Fusion Glycoprotein (F). Journal of Biological Chemistry, 284(3), 1628-1635.
  • University of California, Dept. of MIMG, David Geffen School Medical, 257 BSRB, 615 Charles E Young Dr. E, Los Angeles, CA 90095, USA.
  • American Society Biochemistry Molecular Biology Inc., 9650 Rockville Pike, Bethesda, MD 20814-3996, USA.
  • Virus Weekly, 2009.

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