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The complete influenza hemagglutinin fusion domain adopts a tight helical hairpin arrangement at the lipid:water interface.

ABSTRACT: All but five of the N-terminal 23 residues of the HA2 domain of the influenza virus glycoprotein hemagglutinin (HA) are strictly conserved across all 16 serotypes of HA genes. The structure and function of this HA2 fusion peptide (HAfp) continues to be the focus of extensive biophysical, computational, and functional analysis, but most of these analyses are of peptides that do not include the strictly conserved residues Trp(21)-Tyr(22)-Gly(23). The heteronuclear triple resonance NMR study reported here of full length HAfp of sero subtype H1, solubilized in dodecylphosphatidyl choline, reveals a remarkably tight helical hairpin structure, with its N-terminal alpha-helix (Gly(1)-Gly(12)) packed tightly against its second alpha-helix (Trp(14)-Gly(23)), with six of the seven conserved Gly residues at the interhelical interface. The seventh conserved Gly residue in position 13 adopts a positive angle, enabling the hairpin turn that links the two helices. The structure is stabilized by multiple interhelical C(alpha)H to C=O hydrogen bonds, characterized by strong interhelical H(N)-H(alpha) and H(alpha)-H(alpha) NOE contacts. Many of the previously identified mutations that make HA2 nonfusogenic are also incompatible with the tight antiparallel hairpin arrangement of the HAfp helices.(15)N relaxation analysis indicates the structure to be highly ordered on the nanosecond time scale, and NOE analysis indicates HAfp is located at the water-lipid interface, with its hydrophobic surface facing the lipid environment, and the Gly-rich side of the helix-helix interface exposed to solvent.

SUBMITTER: Lorieau JL

PROVIDER: S-EPMC2895095 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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The complete influenza hemagglutinin fusion domain adopts a tight helical hairpin arrangement at the lipid:water interface.

Lorieau Justin L JL Louis John M JM Bax Ad A

Proceedings of the National Academy of Sciences of the United States of America 20100602 25

All but five of the N-terminal 23 residues of the HA2 domain of the influenza virus glycoprotein hemagglutinin (HA) are strictly conserved across all 16 serotypes of HA genes. The structure and function of this HA2 fusion peptide (HAfp) continues to be the focus of extensive biophysical, computational, and functional analysis, but most of these analyses are of peptides that do not include the strictly conserved residues Trp(21)-Tyr(22)-Gly(23). The heteronuclear triple resonance NMR study report ...[more]

PMID: 20534508

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Project description:Enveloped viruses are surrounded by a membrane which is obtained from an infected host cell during budding. Infection of a new cell requires joining (fusion) of the virus and cell membranes. This process is mediated by a monotopic viral fusion protein with a large ectodomain outside the virus. The ectodomains of class I enveloped viruses have a N-terminal "fusion peptide" (fp) domain that is critical for fusion and binds to the cell membrane. In this study, 2H NMR spectra are analyzed for deuterated membrane with fp from either HIV gp41 (GP) or influenza hemagglutinin (HA) fusion proteins. In addition, the HAfp samples are studied at more fusogenic pH 5 and less fusogenic pH 7. GPfp adopts intermolecular antiparallel β sheet structure whereas HAfp is a monomeric helical hairpin. The data are obtained for a set of temperatures between 35 and 0 °C using DMPC-d54 lipid with perdeuterated acyl chains. The DMPC has liquid-crystalline (Lα) phase with disordered chains at higher temperature and rippled gel (Pβ') or gel phase (Lβ') with ordered chains at lower temperature. At given temperature T, the no peptide and HAfp, pH 7 samples exhibit similar spectral lineshapes. Spectral broadening with reduced temperature correlates with the transition from Lα to Pβ' and then Lβ' phases. At given T, the lineshapes are narrower for HAfp, pH 5 vs. no peptide and HAfp, pH 7 samples, and even narrower for the GPfp sample. These data support larger-amplitude fast (>105 Hz) lipid acyl chain motion for samples with fusogenic peptides, and peptide interference with chain ordering. The NMR data of the present paper correlate with insertion of these peptides into the hydrocarbon core of the membrane and support a significant fusion contribution from the resultant lipid acyl chain disorder, perhaps because of reduced barriers between the different membrane topologies in the fusion pathway. Membrane insertion and lipid perturbation appear common to both β sheet and helical hairpin peptides.

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The complete influenza hemagglutinin fusion domain adopts a tight helical hairpin arrangement at the lipid:water interface.

Publications

The complete influenza hemagglutinin fusion domain adopts a tight helical hairpin arrangement at the lipid:water interface.

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