Résumé
The rabies and Ebola viruses recruit the highly conserved host protein LC8 for their own reproductive success. in vivo knockouts of the LC8 recognition motif within the rabies virus phosphoprotein (RavP) result in completely non-lethal viral infections. In this work, we provide a model for the molecular role LC8 plays in viral lethality. We show that RavP and LC8 co-localize in rabies infected cells, and that LC8 interactions are essential for efficient viral polymerase activity. NMR, SAXS, and molecular modeling demonstrate that LC8 binding to a disordered linker adjacent to an endogenous dimerization domain results in restrictions in RavP domain orientations. The resulting dynamic RavP-LC8 tetrameric complex is similar to that of a related phosphoprotein that does not bind LC8, suggesting a regulatory role for the LC8-induced structure. The high conservation of the LC8 motif in Lyssavirus phosphoproteins evinces a broader purpose for LC8 in regulating vital downstream phosphoprotein functions.