Oligomerization of fusogenic peptides promotes membrane fusion by enhancing membrane destabilization.
A key element of membrane fusion reactions in biology is the involvement of specific fusion proteins. In many viruses, the proteins that mediate membrane fusion usually exist as homotrimers. Furthermore, they contain extended triple-helical coiled-coil domains and fusogenic peptides. It has been suggested that the coiled-coil domains present the fusogenic peptide in a conformation or geometry favorable for membrane fusion. To test the hypothesis that trimerization of fusogenic peptide is related to optimal fusion, we have designed and synthesized a triple-stranded coiled-coil X31 peptide, also known as the ccX31, which mimics the influenza virus hemagglutinin fusion peptide in the fusion-active state. We compared the membrane interactive properties of ccX31 versus the monomeric X31 fusogenic peptide. Our data show that trimerization enhances peptide-induced leakage of liposomal contents and lipid mixing. Furthermore, studies using micropipette aspiration of single vesicles reveal that ccX31 decreases lysis tension, tau(lysis), but not area expansion modulus, Ka, of phospholipid bilayers, whereas monomeric X31 peptide lowers both tau(lysis) and Ka. Our results are consistent with the hypothesis that oligomerization of fusogenic peptide promotes membrane fusion, possibly by enhancing localized destabilization of lipid bilayers.
Lau
Wai Leung
WL
Department of Biochemistry and Molecular Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Ege
David S
DS
Lear
James D
JD
Hammer
Daniel A
DA
DeGrado
William F
WF
D019281:Dimerization; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry*; D046911:Macromolecular Substances; D008560:Membrane Fluidity; D008561:Membrane Fusion; D008563:Membrane Lipids / Q000737:chemistry*; D008567:Membranes, Artificial; D008968:Molecular Conformation; D010539:Permeability; D010743:Phospholipids / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014760:Viral Fusion Proteins / Q000737:chemistry*
D019267:Hemagglutinin Glycoproteins, Influenza Virus; D008081:Liposomes; D046911:Macromolecular Substances; D008563:Membrane Lipids; D008567:Membranes, Artificial; D010743:Phospholipids; D014760:Viral Fusion Proteins