Direct Visualization of the Conformational Dynamics of Single Influenza Hemagglutinin Trimers

Dibyendu Kumar Das, Ramesh Govindan, Ivana Nikić-Spiegel, Florian Krammer, Edward A. Lemke, James B. Munro

Research output: Contribution to journalArticlepeer-review

95 Scopus citations


Influenza hemagglutinin (HA) is the canonical type I viral envelope glycoprotein and provides a template for the membrane-fusion mechanisms of numerous viruses. The current model of HA-mediated membrane fusion describes a static “spring-loaded” fusion domain (HA2) at neutral pH. Acidic pH triggers a singular irreversible conformational rearrangement in HA2 that fuses viral and cellular membranes. Here, using single-molecule Förster resonance energy transfer (smFRET)-imaging, we directly visualized pH-triggered conformational changes of HA trimers on the viral surface. Our analyses reveal reversible exchange between the pre-fusion and two intermediate conformations of HA2. Acidification of pH and receptor binding shifts the dynamic equilibrium of HA2 in favor of forward progression along the membrane-fusion reaction coordinate. Interaction with the target membrane promotes irreversible transition of HA2 to the post-fusion state. The reversibility of HA2 conformation may protect against transition to the post-fusion state prior to arrival at the target membrane. Single-molecule FRET is used to provide real-time visualization of influenza hemagglutinin conformational dynamics on the viral surface during triggering by low pH.

Original languageEnglish
Pages (from-to)926-937.e12
Issue number4
StatePublished - 9 Aug 2018


  • membrane fusion
  • protein dynamics
  • single-molecule fluorescence
  • smFRET
  • virus entry


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