page 833, Markovic et al. argue that teamwork is the order of the day in the widely studied model of influenza virus hemagglutinin (HA)-mediated fusion, and suggest that similar cooperative mechanisms may be a general feature of membrane fusion.
At low pH, trimers of HA undergo a conformational transition to mediate fusion between the viral envelope membrane and the membrane of a lysosome, allowing the virus to enter the cytoplasm. Using several approaches in different systems, the authors varied the density of HA trimers on membrane surfaces and measured the speed and efficiency of the conformational transition. Although HA from two different viral strains exhibited different rates of activation, an increase in HA density always correlated with an increase in the percentage of activated HA, indicating positive cooperativity between HA trimers during activation.
Markovic et al. propose that individual HA trimers establish a transient early state, which then promotes the transition of neighboring trimers, causing activation to spread cooperatively. HA becomes concentrated in the contact zone because of its tendency to attach to the target membrane. At these higher HA densities in the contact zone, the probability of activation would increase because each complex would be closer to neighbors that could promote the transition to fusion-competence through lateral contact. This mechanism would reduce the probability of premature HA activation, and would also allow the trimers to coordinate the release of energy that accompaniestheir conformational change, bringing about membrane fusion. Besides providing a general model for membrane fusion, cooperative activation might also help explain the behavior of immune complexes and other multimeric assemblies operating in the plane of a membrane. ▪