A core trimer of the paramyxovirus fusion protein: Parallels to influenza virus hemagglutinin and HIV-1 gp41

Sangeeta Bagai Joshi, Rebecca Ellis Dutch, Robert A. Lamb

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154 Scopus citations

Abstract

The paramyxovirus fusion (F) protein mediates membrane fusion. The biologically active F protein consists of a membrane distal subunit, F2, and a membrane-anchored subunit, F1. We have identified a highly stable structure composed of peptides derived from the F1 heptad repeat A, which abuts the hydrophobic fusion peptide (peptide N-1), and the F1 heptad repeat B, located 270 residues downstream and adjacent to the transmembrane domain (peptides C-1 and C-2). In isolation, peptide N-1 is 47% α-helical and peptide C-1 and C-2 are unfolded. When mixed together, peptides N1 + C1 form a thermostable (T(m) >90°C), 82% α-helical, discrete trimer of heterodimers (mass 31,300 M(r)) that is resistant to denaturation by 2% SDS at 40°C. We suggest that this α-helical trimeric complex represents the core most stable form of the F protein that either is fusion competent or forms after fusion has occurred. Peptide C-1 is a potent inhibitor of both the lipid mixing and the aqueous content mixing fusion activity of the SV5 F protein. In contrast, peptides N-1 and N-2 inhibit cytoplasmic content mixing but not lipid mixing, leading to a stable hemifusion state. Thus, these peptides define functionally different steps in the fusion process. The parallels among both the fusion processes and the protein structures of paramyxovirus F proteins, HIV gp41, and influenza virus hemagglutinin are discussed, as the analogies are indicative of a conserved paradigm for fusion promotion among fusion proteins from widely disparate viruses.

Original languageEnglish
Pages (from-to)20-34
Number of pages15
JournalVirology
Volume248
Issue number1
DOIs
StatePublished - Aug 15 1998

Bibliographical note

Funding Information:
We are very grateful to Jonathon Widom and Ted Jardetzky for numerous helpful discussions, to Brian Shoichet for allowing us to use his CD spectrometer and for help in interpreting the data, and to Ruby MacDonald for advice on using the analytical ultracentrifuge. We are grateful to the W. M. Keck Foundation for supporting the Northwestern University Center for Biophysics and to the Northwestern University Chemistry Department Analytical Services Laboratory for mass spectroscopy. This work was supported in part by Research Grant AI-23173 from the National Institute of Allergy and Infectious Disease. R.E.D. is supported by Public Health Service NRSA F32 AI-09607. R.E.D. and S.B. were Associates and R.A.L. is an Investigator of the Howard Hughes Medical Institute.

ASJC Scopus subject areas

  • Virology

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