Journal
JOURNAL OF CELL BIOLOGY
Volume 163, Issue 2, Pages 363-374Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200305130
Keywords
viral fusion proteins; membrane fusion activation; molecular models; protein conformation; antiviral agents
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Funding
- NIAID NIH HHS [R01 AI023173, AI-23173] Funding Source: Medline
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Many viral fusion-mediating glycoproteins couple alpha-helical bundle formation to membrane merger, but have different methods for fusion activation. To study paramyxovirus-mediated fusion, we mutated the SV5 fusion (F) protein at conserved residues L447 and 1449, which are adjacent to heptad repeat (HR) B and bind to a prominent cavity in the HRA trimeric coiled coil in the fusogenic six-helix bundle (6HB) structure. These analyses on residues L447 and 1449, both in intact F protein and in 6HB, suggest a metamorphic region around these residues with dual structural roles. Mutation of L447 and 1449 to aliphatic residues destabilizes the 6HB structure and attenuates fusion activity. Mutation of L447 and 1449 to aromatic residues also destabilizes the 6HB structure despite promoting hyperactive fusion, indicating that 6HB stability alone does not dictate fusogenicity. Thus, residues L447 and 1449 adjacent to HRB in paramyxovirus F have distinct roles in fusion activation and 6HB formation, suggesting this region is involved in a conformational switch.
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