Soluble ectodomain of rabies virus glycoprotein expressed in eukaryotic cells folds in a monomeric conformation that is antigenically distinct from the native state of the complete, membrane-anchored glycoprotein

Rabies virus glycoprotein (G) is a trimeric type I transmembrane glycoprote in that mediates both virus receptor recognition and low pH-induced membran e fusion, G can assume three different states: the 'native' state (N) detec ted at the virus surface, which is responsible for receptor binding, the ac tivated hydrophobic state (A), which interacts with the target membrane as a first step in the fusion process, and the fusion-inactive conformation (I ), These three states, which are structurally different, are in a pH-depend ent equilibrium. This equilibrium is shifted toward the I state at low pH, This paper includes an investigation of the structure of the ectodomain of the PV strain of rabies virus when it is synthesized as a soluble form (G(1 -439)) lacking the transmembrane and intracytoplasmic domains (residues 440 -505). It is shown that, whatever the extracellular pH, G(1-439) is secrete d as a monomer that has the antigenic characteristics of the I state, This I-like state is not acquired in the acidic compartments of the Golgi but di rectly in the endoplasmic reticulum, Finally, membrane anchorage by the G t ransmembrane domain (G(1-461)) is sufficient for the G ectodomain to be fol ded into the native N form. These results emphasize the role of the G trans membrane domain in the correct folding of the ectodomain.