Single residue deletions along the length of the influenza HA fusion peptide lead to inhibition of membrane fusion function

Virology. 2009 Nov 25;394(2):321-30. doi: 10.1016/j.virol.2009.08.031. Epub 2009 Sep 15.

Abstract

A panel of eight single amino acid deletion mutants was generated within the first 24 residues of the fusion peptide domain of the of the hemagglutinin (HA) of A/Aichi/2/68 influenza A virus (H3N2 subtype). The mutant HAs were analyzed for folding, cell surface transport, cleavage activation, capacity to undergo acid-induced conformational changes, and membrane fusion activity. We found that the mutant DeltaF24, at the C-terminal end of the fusion peptide, was expressed in a non-native conformation, whereas all other deletion mutants were transported to the cell surface and could be cleaved into HA1 and HA2 to activate membrane fusion potential. Furthermore, upon acidification these cleaved HAs were able to undergo the characteristic structural rearrangements that are required for fusion. Despite this, all mutants were inhibited for fusion activity based on two separate assays. The results indicate that the mutant fusion peptide domains associate with target membranes in a non-functional fashion, and suggest that structural features along the length of the fusion peptide are likely to be relevant for optimal membrane fusion activity.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Cricetinae
  • Genes, Viral
  • Hemagglutinin Glycoproteins, Influenza Virus / chemistry
  • Hemagglutinin Glycoproteins, Influenza Virus / genetics*
  • Hemagglutinin Glycoproteins, Influenza Virus / physiology*
  • Humans
  • Hydrogen-Ion Concentration
  • Influenza A Virus, H3N2 Subtype / genetics*
  • Influenza A Virus, H3N2 Subtype / physiology*
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Conformation
  • Protein Structure, Quaternary
  • Sequence Deletion*
  • Sequence Homology, Amino Acid
  • Viral Fusion Proteins / chemistry
  • Viral Fusion Proteins / genetics*
  • Viral Fusion Proteins / physiology*
  • Virus Internalization*

Substances

  • Hemagglutinin Glycoproteins, Influenza Virus
  • Viral Fusion Proteins