title: Fusion peptide of influenza hemagglutinin requires a fixed angle boomerang structure for activity.
abstract: The fusion peptide of influenza hemagglutinin is crucial for cell entry of this virus. Previous studies showed that this peptide adopts a boomerang-shaped structure in lipid model membranes at the pH of membrane fusion. To examine the role of the boomerang in fusion, we changed several residues proposed to stabilize the kink in this structure and measured fusion. Among these, mutants E11A and W14A expressed hemagglutinins with hemifusion and no fusion activities, and F9A and N12A had no effect on fusion, respectively. Binding enthalpies and free energies of mutant peptides to model membranes and their ability to perturb lipid bilayer structures correlated well with the fusion activities of the parent full-length molecules. The structure of W14A determined by NMR and site-directed spin labeling features a flexible kink that points out of the membrane, in sharp contrast to the more ordered boomerang of the wild-type, which points into the membrane. A specific fixed angle boomerang structure is thus required to support membrane fusion.
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Alex L
authors.initials: AL
authors.lastname: Lai
authors.forename: Heather
authors.initials: H
authors.lastname: Park
authors.forename: Judith M
authors.initials: JM
authors.lastname: White
authors.forename: Lukas K
authors.initials: LK
authors.lastname: Tamm
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology / Q000821:virology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007251:Influenza, Human; D008051:Lipid Bilayers / Q000737:chemistry; D008561:Membrane Fusion / Q000502:physiology*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D013113:Spin Labels
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D008051:Lipid Bilayers; D010455:Peptides; D013113:Spin Labels