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Spring-loaded heptad repeat residues regulate the expression and activation of paramyxovirus fusion protein

Laura E Luque1, Charles J Russell

  • 1Department of Infectious Diseases, MS 320, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794, USA.

Journal of Virology
|January 26, 2007
PubMed

Insights

Mutations in the paramyxovirus fusion (F) protein’s heptad repeat A region reveal key regulators of viral membrane fusion. Some mutations impaired F protein function, while others enhanced it, offering insights into fusion regulation.

Area of Science:

  • Virology
  • Structural Biology
  • Molecular Biology

Background:

  • Paramyxovirus fusion (F) protein mediates viral entry by fusing the viral envelope with cellular membranes.
  • The F protein, a class I viral fusion glycoprotein, contains heptad repeat regions (HRA and HRB) crucial for membrane fusion and potential antiviral targets.
  • Upon activation, F protein's HRA refolds into a coiled coil, driving membrane fusion through a fusogenic hairpin intermediate.

Purpose of the Study:

  • To investigate the regulation of F protein conformational changes during viral fusion.
  • To identify key residues within the HRA region that control F protein refolding and fusogenicity.
  • To explore the role of conserved and non-conserved residues in HRA function.

Main Methods:

  • Site-directed mutagenesis of a conserved 10-residue sequence in the Sendai virus F protein's HRA region.
  • Analysis of F protein expression, processing, and fusogenicity following mutations.
  • Assessment of the structural and functional impact of mutations on protein refolding and membrane fusion.

Main Results:

  • Fifteen mutations were introduced into the HRA region of the Sendai virus F protein.
  • Nine mutations resulted in significant defects in F protein expression, processing, and fusogenicity.
  • Six mutations enhanced F protein fusogenicity, suggesting they facilitate HRA coil refolding.
  • Residues not typically involved in coiled-coil formation were identified as critical regulators of F protein folding and fusion activity.

Conclusions:

  • The study demonstrates that specific residues within the HRA region, including non-conserved ones, play critical roles in regulating F protein expression, folding, and fusogenic activity.
  • Dramatic structural changes in the F protein between prefusion and hairpin conformations are regulated by specific regions, impacting protein activation.
  • Findings provide insights into the mechanism of paramyxovirus-mediated membrane fusion and potential strategies for antiviral development.

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