pH-triggered, activated-state conformations of the influenza hemagglutinin fusion peptide revealed by NMR

Proc Natl Acad Sci U S A. 2012 Dec 4;109(49):19994-9. doi: 10.1073/pnas.1213801109. Epub 2012 Nov 19.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Sequence
  • Hemagglutinins, Viral / chemistry*
  • Hemagglutinins, Viral / genetics
  • Hemagglutinins, Viral / isolation & purification*
  • Hydrogen-Ion Concentration
  • Membrane Fusion / physiology*
  • Models, Molecular*
  • Molecular Sequence Data
  • Mutation / genetics
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Conformation*
  • Virus Internalization*

Substances

  • Hemagglutinins, Viral
  • hemagglutinin HA-2 fusogenic peptide, Influenza virus

Associated data

  • PDB/2LWA