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Journal article

Efficient replication of a paramyxovirus independent of full zippering of the fusion protein six-helix bundle domain.

  • Brindley MA Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303; and.
  • Plattet P Neurovirology Unit, Division of Experimental Clinical Research, Veterinary Public Health, Vetsuisse Faculty, University of Bern, CH-3012 Bern, Switzerland.
  • Plemper RK Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303; and rplemper@gsu.edu.
  • 2014-08-27
Published in:
  • Proceedings of the National Academy of Sciences of the United States of America. - 2014
measles virus
membrane fusion
Amino Acid Sequence
Animals
COS Cells
Chickens
Chlorocebus aethiops
Cysteine
Disulfides
Humans
Kinetics
Measles virus
Models, Molecular
Molecular Sequence Data
Mutant Proteins
Protein Engineering
Protein Multimerization
Protein Refolding
Protein Stability
Protein Structure, Secondary
Protein Structure, Tertiary
Recombination, Genetic
Viral Fusion Proteins
Virus Replication
English Enveloped viruses such as HIV and members of the paramyxovirus family use metastable, proteinaceous fusion machineries to merge the viral envelope with cellular membranes for infection. A hallmark of the fusogenic glycoproteins of these pathogens is refolding into a thermodynamically highly stable fusion core structure composed of six antiparallel α-helices, and this structure is considered instrumental for pore opening and/or enlargement. Using a paramyxovirus fusion (F) protein, we tested this paradigm by engineering covalently restricted F proteins that are predicted to be unable to close the six-helix bundle core structure fully. Several candidate bonds formed efficiently, resulting in F trimers and higher-order complexes containing covalently linked dimers. The engineered F complexes were incorporated into recombinant virions efficiently and were capable of refolding into a postfusion conformation without temporary or permanent disruption of the disulfide bonds. They efficiently formed fusion pores based on virus replication and quantitative cell-to-cell and virus-to-cell fusion assays. Complementation of these F mutants with a monomeric, fusion-inactive F variant enriched the F oligomers for heterotrimers containing a single disulfide bond, without affecting fusion complementation profiles compared with standard F protein. Our demonstration that complete closure of the fusion core does not drive paramyxovirus entry may aid the design of strategies for inhibiting virus entry.
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  • English
Open access status
bronze
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https://sonar.ch/global/documents/56484
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