Switching between Successful and Dead-End Intermediates in Membrane Fusion

Abstract

Fusion of cellular membranes during normal biological processes, including proliferation, or synaptic transmission, is mediated and controlled by sophisticated protein machinery ensuring the preservation of the vital barrier function of the membrane throughout the process. Fusion of virus particles with host cell membranes is more sparingly arranged and often mediated by a single fusion protein, and the virus can afford to be less discriminative towards the possible different outcomes of fusion attempts. Formation of leaky intermediates was recently observed in some fusion processes, and an alternative trajectory of the process involving formation of π-shaped structures was suggested. In this study, we apply the methods of elasticity theory and Lagrangian formalism augmented by phenomenological and molecular geometry constraints and boundary conditions to investigate the traits of this trajectory and the drivers behind the choice of one of the possible scenarios depending on the properties of the system. The alternative pathway proved to be a dead end, and, depending on the parameters of the participating membranes and fusion proteins, the system can either reversibly enter the corresponding “leaky” configuration or be trapped in it. A parametric study in the biologically relevant range of variables emphasized the fusion protein properties crucial for the choice of the fusion scenario.

Phosphatidylcholine Membrane Fusion Is pH-Dependent

“…This fusion mechanism was experimentally demonstrated for a number of systems, including purely lipidic [ 16 , 18 , 19 , 20 ] and lipid-protein [ 21 , 22 , 23 , 24 , 25 ] systems. Although there are other possible ways of evolution of the system of fusing membranes, sometimes occurring with the rupture of one of the interacting membranes at the intermediate stage [ 26 , 27 ], it is the trajectory associated with radial expansion of intermediate stalk that proved to be highly efficient, whereas others do not result in complete fusion, i.e., they lead to a dead end [ 27 ]. In this respect, it is the lipid component of the biological membranes that plays an important role in fusion.…”

Lateral Membrane Heterogeneity Regulates Viral-Induced Membrane Fusion during HIV Entry

“…The equilibrium distance H 0 between the membranes is determined by the balance of hydration repulsion forces and the attraction induced by fusion peptides, and it can vary depending on the number of proteins in the fusion rosette and on the curvature of the membranes undergoing fusion. According to various estimates [ 17 , 20 , 51 ], this value is of the order of several nanometers. According to Figure 5 , small H 0 values correspond to the situation when rafts are not favorable for fusion, while the large values—to the situation when rafts facilitate it.…”

“…In this paper, we theoretically show that in the case of HIV, insertion of viral fusion peptide into the region of the raft boundary promotes viral fusion. In our work, we use a mechanistic approach for the membrane description successfully used for theoretical investigation of various membrane systems [ 8 , 9 , 11 , 16 , 17 ]. In the framework of this approach, the insertion of any peptide into the membrane is described by the averaged geometric characteristics: depth and width of the insertion.…”

“…Earlier, we have demonstrated that there is a strong correlation between the depth of the viral fusion peptide incorporation into a monolayer of the target cell membrane (which is equivalent to generation of the membrane curvature) and the height of the energy barrier for virus-induced membrane fusion [ 16 , 17 ]. According to the generally adopted theory, membrane fusion occurs in several stages [ 18 ].…”

The Effect of Transmembrane Protein Shape on Surrounding Lipid Domain Formation by Wetting

“…All expressions were obtained analytically, but we do not provide them because of their extreme bulkiness. The methodology for finding elastic energy is described in more detail in [69,70,71].…”