Characterization of the equilibrium between the native and fusion-inactive conformation of rabies virus glycoprotein indicates that the fusion complex is made of several trimers.

Rabies virus-induced membrane fusion is triggered at low pH and is mediated by the trimeric viral glycoprotein (G). G assumes three conformations: the native state (N) detected above pH 7; the activated state (A), which initiates the fusion process; and the fusion-inactive conformation (I) observed after prolonged incubation at low pH. Differently from other viral fusogenic glycoproteins, G in the I state recovers its native conformation when reincubated above pH 7. Here, we demonstrate that there is a thermodynamic equilibrium between the different states of G between pH 6 and pH 7.5. The study of this equilibrium at various pH values indicated that the conformational change toward I is induced by the protonation of at least three residues per trimer. Finally, studies on the mechanism leading to low pH induced fusion inactivation indicated that a large number of G molecules is required for stable hydrophobic interaction of the virus with the target membrane. (c) 2002 Elsevier Science (USA).