A hydrophobic target: Using the paramyxovirus fusion protein transmembrane domain to modulate fusion protein stability

Chelsea T. Barrett, Stacy R. Webb, Rebecca Ellis Dutch

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Enveloped viruses utilize surface glycoproteins to bind and fuse with a target cell membrane. The zoonotic Hendra virus (HeV), a member of the family Paramyxoviridae, utilizes the attachment protein (G) and the fusion protein (F) to perform these critical functions. Upon triggering, the trimeric F protein undergoes a large, irreversible conformation change to drive membrane fusion. Previously, we have shown that the transmembrane (TM) domain of the F protein, separate from the rest of the protein, is present in a monomer-trimer equilibrium. This TM-TM association contributes to the stability of the prefusion form of the protein, supporting a role for TM-TM interactions in the control of F protein conformational changes. To determine the impact of disrupting TM-TM interactions, constructs expressing the HeV F TM with limited flanking sequences were synthesized. Coexpression of these constructs with HeV F resulted in dramatic reductions in the stability of F protein expression and fusion activity. In contrast, no effects were observed when the HeV F TM constructs were coexpressed with the nonhomologous parainfluenza virus 5 (PIV5) fusion protein, indicating a requirement for specific interactions. To further examine this, a TM peptide homologous to the PIV5 F TM domain was synthesized. Addition of the peptide prior to infection inhibited infection with PIV5 but did not significantly affect infection with human metapneumovirus, a related virus. These results indicate that targeted disruption of TM-TM interactions significantly impact viral fusion protein stability and function, presenting these interactions as a novel target for antiviral development. IMPORTANCE Enveloped viruses require virus-cell membrane fusion to release the viral genome and replicate. The viral fusion protein triggers from the pre- to the postfusion conformation, an essentially irreversible change, to drive membrane fusion. We found that small proteins containing the TM and a limited flanking region homologous to the fusion protein of the zoonotic Hendra virus reduced protein expression and fusion activity. The introduction of exogenous TM peptides May displace a TM domain, disrupting native TM-TM interactions and globally destabilizing the fusion protein. Supporting this hypothesis, we showed that a sequence-specific transmembrane peptide dramatically reduced viral infection in another enveloped virus model, suggesting a broader inhibitory mechanism. Viral fusion protein TM-TM interactions are important for protein function, and disruption of these interactions dramatically reduces protein stability.

Original languageEnglish
Article numbere00863-19
JournalJournal of Virology
Issue number17
StatePublished - Sep 1 2019

Bibliographical note

Funding Information:
We thank the Dutch laboratory for input on the manuscript. This work was supported by NIAID grant R01AI051517 and NIH grant 2P20 RR02017 to R.E.D. and an NRSA grant (F31 AI120653) to S.R.W.

Publisher Copyright:
© 2019 American Society for Microbiology. All Rights Reserved.


  • Antiviral agents
  • Fusion protein
  • Membrane fusion
  • Transmembrane domain

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology


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