The paramyxovirus fusion protein forms an extremely stable core trimer: structural parallels to influenza virus haemagglutinin and HIV-1 gp41

The paramyxovirus fusion (F) protein mediates membrane fusion. The biologic ally active F protein consists of a membrane distal subunit F-2 and a membr ane anchored subunit F-1. A highly stable structure has been identified com prised of peptides derived from the simian virus 5 (SV5) F-1 heptad repeat A, which abuts the hydrophobic fusion peptide (peptide N-1), and the SV5 F- 1 heptad repeat B, located 270 residues downstream and adjacent to the tran smembrane domain (peptides C-l and C-2). In isolation, peptide N-1 is 47% a lpha-helical and peptide C-l and C-2 are unfolded. When mixed together, pep tides N1+C1 form a thermostable (T-m>90 degrees C), 82% alpha-helical, disc rete trimer of heterodimers (mass 31 300 M-r) that is resistant to denatura tion by 2% SDS at 40 degrees C. The authors suggest that this alpha-helical trimeric complex represents the core most stable form of the F protein tha t is either fusion competent or forms after fusion has occurred. Peptide C- 1 is a potent inhibitor of both the lipid mixing and aqueous content mixing fusion activity of the SV5 5 protein. In contrast, peptide N-1 inhibits cy toplasmic content mixing but not lipid mixing, leading to a stable hemifusi on state. Thus, these peptides define functionally different steps in the f usion process. The parallels among both the fusion processes and the protei n structures of paramyxovirus F proteins, HIV gp41 and influenza virus haem agglutinin are discussed, as the analogies are indicative of a conserved pa radigm for fusion promotion among fusion proteins from widely disparate vir uses.