title: Membrane structure and fusion-triggering conformational change of the fusion domain from influenza hemagglutinin.
abstract: The N-terminal domain of the influenza hemagglutinin (HA) is the only portion of the molecule that inserts deeply into membranes of infected cells to mediate the viral and the host cell membrane fusion. This domain constitutes an autonomous folding unit in the membrane, causes hemolysis of red blood cells and catalyzes lipid exchange between juxtaposed membranes in a pH-dependent manner. Combining NMR structures determined at pHs 7.4 and 5 with EPR distance constraints, we have deduced the structures of the N-terminal domain of HA in the lipid bilayer. At both pHs, the domain is a kinked, predominantly helical amphipathic structure. At the fusogenic pH 5, however, the domain has a sharper bend, an additional 3(10)-helix and a twist, resulting in the repositioning of Glu 15 and Asp 19 relative to that at the nonfusogenic pH 7.4. Rotation of these charged residues out of the membrane plane creates a hydrophobic pocket that allows a deeper insertion of the fusion domain into the core of the lipid bilayer. Such an insertion mode could perturb lipid packing and facilitate lipid mixing between juxtaposed membranes.
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22908-0736, USA.
authors.forename: X
authors.initials: X
authors.lastname: Han
authors.forename: J H
authors.initials: JH
authors.lastname: Bushweller
authors.forename: D S
authors.initials: DS
authors.lastname: Cafiso
authors.forename: L K
authors.initials: LK
authors.lastname: Tamm
mesh_terms: D000595:Amino Acid Sequence; D002942:Circular Dichroism; D003902:Detergents / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D008561:Membrane Fusion; D008823:Micelles; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D009975:Orthomyxoviridae / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
chemical_list: D003902:Detergents; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D008051:Lipid Bilayers; D008081:Liposomes; D008823:Micelles; D010446:Peptide Fragments