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...

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