Nipah Virus Entry into Host Cell: Inter-Monomer Rearrangement Signaled by Receptor Binding at Allosteric Site

Paramyxoviruses cause numerous diseases in humans and farm animals. Their entry into host cells is facilitated by the concerted action of two of their membrane glycoproteins - the attachment protein, which binds host receptors, and the fusion protein (F) that mediates virus-host membrane fusion. The attachment proteins have separate receptor binding domain (RBD) and F-activation domain separated by u003e 2 nm. However, little is known about the mechanism of allosteric coupling between these domains, and how the F-activating domain activates F. Here we investigate a recent proposition for the Nipah virus, an emerging, highly-lethal member of the paramyxovirus family. Experiments and simulations suggest the likelihood that the binding of host receptor to the RBD alters the interface between two RBDs of the attachment protein, and in a manner that enhances the exposure of the F-activation domain, allowing it to activate F. This proposition is intriguing because the RBDs themselves undergo only minor receptor-induced structural changes, and the receptor-RBD interface is not contiguous with the RBD-RBD interface. We address this through a combination of standard and enhanced conformational sampling molecular mechanics simulations. We find that despite inducing only minor changes in individual RBDs, receptor binding indeed alters the RBD-RBD interface significantly. Also, the nature of the change is such that ephrin-binding enhances exposure of the F-activating domain. While this finding is in line with the proposed model, the causality between enhanced exposure of the F-activating domain and F-activation still remains to be established. We also find that the proposed interface between the RBD-RBD dimer and the F-activating domain contains a cluster of residues whose conformational ensembles are modified by receptor binding, which suggests a possible mechanistic role of this interface.