title: pH-triggered, activated-state conformations of the influenza hemagglutinin fusion peptide revealed by NMR.
abstract: The highly conserved first 23 residues of the influenza hemagglutinin HA2 subunit constitute the fusion domain, which plays a pivotal role in fusing viral and host-cell membranes. At neutral pH, this peptide adopts a tight helical hairpin wedge structure, stabilized by aliphatic hydrogen bonding and charge-dipole interactions. We demonstrate that at low pH, where the fusion process is triggered, the native peptide transiently visits activated states that are very similar to those sampled by a G8A mutant. This mutant retains a small fraction of helical hairpin conformation, in rapid equilibrium with at least two open structures. The exchange rate between the closed and open conformations of the wild-type fusion peptide is ~40 kHz, with a total open-state population of ~20%. Transitions to these activated states are likely to play a crucial role in formation of the fusion pore, an essential structure required in the final stage of membrane fusion.
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Lorieau
authors.forename: John M
authors.initials: JM
authors.lastname: Louis
authors.forename: Charles D
authors.initials: CD
authors.lastname: Schwieters
authors.forename: Adriaan
authors.initials: A
authors.lastname: Bax
mesh_terms: D000595:Amino Acid Sequence; D006389:Hemagglutinins, Viral / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification*; D006863:Hydrogen-Ion Concentration; D008561:Membrane Fusion / Q000502:physiology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D053586:Virus Internalization
chemical_list: D006389:Hemagglutinins, Viral; C452559:hemagglutinin HA-2 fusogenic peptide, Influenza virus