Design and function of a conformationally restricted analog of the influenza virus fusion peptide.
A conformationally restricted analog of the N-terminal 12-residue peptide segment of the HA2 subunit of the PPV/34, PR/8/34, and Jap/57 strains of influenza virus hemagglutinin was synthesized containing three residues of Calpha-methyl-valine. This peptide has a higher content of helical structure in the presence of 50% trifluoroethanol or when interacting with liposomes of egg phosphatidylcholine compared with the conformationally more flexible control peptide with the native sequence. The control and analog peptides had opposite effects on membrane curvature as measured by shifts in the bilayer-to-hexagonal phase transition temperature of a synthetic phosphatidylethanolamine derivative. The control peptide promoted more negative curvature, particularly at acidic pH and was also more potent than the analog in promoting lipid mixing. The results indicate that the ability of the peptide to sample a broader range of conformations is required for the influenza fusion peptide to destabilize membranes and that a rigid helical structure is less fusogenic. The difference between the two peptides and between pH 7.4 and pH 5.0 show a correlation between the ability to promote negative curvature and to accelerate lipid mixing.
Bertocco
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A
Institute of Biomolecular Chemistry, CNR, Department of Organic Chemistry, University of Padova, 35131 Padova, Italy.
Formaggio
F
F
Toniolo
C
C
Broxterman
Q B
QB
Epand
R F
RF
Epand
R M
RM
D002152:Calorimetry, Differential Scanning; D002942:Circular Dichroism; D006389:Hemagglutinins, Viral / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008081:Liposomes / Q000737:chemistry; D008561:Membrane Fusion; D008563:Membrane Lipids / Q000737:chemistry; D009975:Orthomyxoviridae / Q000737:chemistry*; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011487:Protein Conformation; D044366:Transition Temperature; D014633:Valine / Q000737:chemistry; D014764:Viral Proteins / Q000737:chemistry*
D006389:Hemagglutinins, Viral; D008081:Liposomes; D008563:Membrane Lipids; D010714:Phosphatidylethanolamines; D014764:Viral Proteins; C458881:hemagglutinin fusogenic peptide, influenza virus; D014633:Valine