A conserved region between the heptad repeats of paramyxovirus fusion proteins is critical for proper F protein folding

Amanda E. Gardner, Kimberly L. Martin, Rebecca E. Dutch

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Paramyxoviruses are a diverse family that utilizes a fusion (F) protein to enter cells via fusion of the viral lipid bilayer with a target cell membrane. Although certain regions of the F protein are known to play critical roles in membrane fusion, the function of much of the protein remains unclear. Sequence alignment of a set of paramyxovirus F proteins and analysis utilizing Block Maker identified a region of conserved amino acid sequence in a large domain between the heptad repeats of F1, designated CBF1. We employed site-directed mutagenesis to analyze the function of completely conserved residues of CBF1 in both the simian virus 5 (SV5) and Hendra virus F proteins. The majority of CBF1 point mutants were deficient in homotrimer formation, proteolytic processing, and transport to the cell surface. For some SV5 F mutants, proteolytic cleavage and surface expression could be restored by expression at 30 °C, and varying levels of fusion promotion were observed at this temperature. In addition, the mutant SV5 F V402A displayed a hyperfusogenic phenotype at both 30 and 37 °C, indicating that this mutation allows for efficient fusion with only an extremely small amount of cleaved, active protein. The recently published prefusogenic structure of PIV5/SV5 F (Yin, H. S., et al. (2006) Nature 439, 38-44) indicates that residues within and flanking CBF1 interact with the fusion peptide domain. Together, these data suggest that CBF1-fusion peptide interactions are critical for the initial folding of paramyxovirus F proteins from this important viral family and can also modulate subsequent membrane fusion promotion.

Original languageEnglish
Pages (from-to)5094-5105
Number of pages12
JournalBiochemistry
Volume46
Issue number17
DOIs
StatePublished - May 1 2007

ASJC Scopus subject areas

  • Biochemistry

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