Line-Tension Controlled Mechanism for Influenza Fusion

Herre Jelger Risselada*, Giovanni Marelli, Marc Fuhrmans, Yuliya G. Smirnova, Helmut Grubmueller, Siewert Jan Marrink, Marcus Mueller

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

58 Citations (Scopus)
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Abstract

Our molecular simulations reveal that wild-type influenza fusion peptides are able to stabilize a highly fusogenic pre-fusion structure, i.e. a peptide bundle formed by four or more trans-membrane arranged fusion peptides. We rationalize that the lipid rim around such bundle has a non-vanishing rim energy (line-tension), which is essential to (i) stabilize the initial contact point between the fusing bilayers, i. e. the stalk, and (ii) drive its subsequent evolution. Such line-tension controlled fusion event does not proceed along the hypothesized standard stalk-hemifusion pathway. In modeled influenza fusion, single point mutations in the influenza fusion peptide either completely inhibit fusion (mutants G1V and W14A) or, intriguingly, specifically arrest fusion at a hemifusion state (mutant G1S). Our simulations demonstrate that, within a line-tension controlled fusion mechanism, these known point mutations either completely inhibit fusion by impairing the peptide's ability to stabilize the required peptide bundle (G1V and W14A) or stabilize a persistent bundle that leads to a kinetically trapped hemifusion state (G1S). In addition, our results further suggest that the recently discovered leaky fusion mutant G13A, which is known to facilitate a pronounced leakage of the target membrane prior to lipid mixing, reduces the membrane integrity by forming a 'super' bundle. Our simulations offer a new interpretation for a number of experimentally observed features of the fusion reaction mediated by the prototypical fusion protein, influenza hemagglutinin, and might bring new insights into mechanisms of other viral fusion reactions.

Original languageEnglish
Article numbere38302
Number of pages14
JournalPLoS ONE
Volume7
Issue number6
DOIs
Publication statusPublished - 28-Jun-2012

Keywords

  • BILAYER-MEMBRANE FUSION
  • MOLECULAR-DYNAMICS
  • PORE FORMATION
  • CONFORMATIONAL-CHANGE
  • TRANSMEMBRANE DOMAIN
  • VIRUS HEMAGGLUTININ
  • CYTOPLASMIC DOMAIN
  • MEDIATED FUSION
  • AREA EXPANSION
  • POINT MUTATION

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