A core trimer of the paramyxovirus fusion protein: parallels to influenza virus hemagglutinin and HIV-1 gp41.
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% alpha-helical and peptide C-1 and C-2 are unfolded. When mixed together, peptides N1 + C1 form a thermostable (Tm >90 degreesC), 82% alpha-helical, discrete trimer of heterodimers (mass 31,300 Mr) that is resistant to denaturation by 2% SDS at 40 degreesC. We suggest that this alpha-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.
Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Illinois, 60208-3500, USA.
S B
SB
Joshi
R E
RE
Dutch
R A
RA
Lamb
D000595:Amino Acid Sequence; D000818:Animals; D002459:Cell Fusion; D002460:Cell Line; D002942:Circular Dichroism; D004912:Erythrocytes / Q000502:physiology; D015700:HIV Envelope Protein gp41 / Q000737:chemistry*; D015497:HIV-1 / Q000378:metabolism; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry*; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D018108:Respirovirus / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics; D014760:Viral Fusion Proteins / Q000096:biosynthesis* / Q000737:chemistry*
D015700:HIV Envelope Protein gp41; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D046911:Macromolecular Substances; D011994:Recombinant Proteins; D014760:Viral Fusion Proteins