Dynamic changes during acid-induced activation of influenza hemagglutinin

Structure. 2015 Apr 7;23(4):665-76. doi: 10.1016/j.str.2015.02.006. Epub 2015 Mar 12.


Influenza hemagglutinin (HA) mediates virus attachment to host cells and fusion of the viral and endosomal membranes during entry. While high-resolution structures are available for the pre-fusion HA ectodomain and the post-fusion HA2 subunit, the sequence of conformational changes during HA activation has eluded structural characterization. Here, we apply hydrogen-deuterium exchange with mass spectrometry to examine changes in structural dynamics of the HA ectodomain at various stages of activation, and compare the soluble ectodomain with intact HA on virions. At pH conditions approaching activation (pH 6.0-5.5) HA exhibits increased dynamics at the fusion peptide and neighboring regions, while the interface between receptor binding subunits (HA1) becomes stabilized. In contrast to many activation models, these data suggest that HA responds to endosomal acidification by releasing the fusion peptide prior to HA1 uncaging and the spring-loaded refolding of HA2. This staged process may facilitate efficient HA-mediated fusion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Hemagglutinin Glycoproteins, Influenza Virus / chemistry*
  • Hemagglutinin Glycoproteins, Influenza Virus / metabolism
  • Hydrogen / metabolism
  • Hydrogen-Ion Concentration
  • Molecular Dynamics Simulation*
  • Molecular Sequence Data
  • Protein Binding
  • Protein Subunits / chemistry


  • Hemagglutinin Glycoproteins, Influenza Virus
  • Protein Subunits
  • Hydrogen