A mechanism of protein-mediated fusion: coupling between refolding of the influenza hemagglutinin and lipid rearrangements.
Although membrane fusion mediated by influenza virus hemagglutinin (HA) is the best characterized example of ubiquitous protein-mediated fusion, it is still not known how the low-pH-induced refolding of HA trimers causes fusion. This refolding involves 1) repositioning of the hydrophobic N-terminal sequence of the HA2 subunit of HA ("fusion peptide"), and 2) the recruitment of additional residues to the alpha-helical coiled coil of a rigid central rod of the trimer. We propose here a mechanism by which these conformational changes can cause local bending of the viral membrane, priming it for fusion. In this model fusion is triggered by incorporation of fusion peptides into viral membrane. Refolding of a central rod exerts forces that pull the fusion peptides, tending to bend the membrane around HA trimer into a saddle-like shape. Elastic energy drives self-assembly of these HA-containing membrane elements in the plane of the membrane into a ring-like cluster. Bulging of the viral membrane within such cluster yields a dimple growing toward the bound target membrane. Bending stresses in the lipidic top of the dimple facilitate membrane fusion. We analyze the energetics of this proposed sequence of membrane rearrangements, and demonstrate that this simple mechanism may explain some of the known phenomenological features of fusion.
Kozlov
M M
MM
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel. misha@devil.tav.ac.il
Chernomordik
L V
LV
D055592:Biophysical Phenomena; D001703:Biophysics; D004548:Elasticity; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008561:Membrane Fusion / Q000502:physiology*; D008563:Membrane Lipids / Q000737:chemistry*; D008954:Models, Biological; D011487:Protein Conformation; D017510:Protein Folding; D013816:Thermodynamics; D014760:Viral Fusion Proteins / Q000737:chemistry
D019267:Hemagglutinin Glycoproteins, Influenza Virus; D008563:Membrane Lipids; D014760:Viral Fusion Proteins