Atomic model of a non-enveloped virus reveals pH sensors for a coordinated process of cell entry

Viruses sense environmental cues (such as pH) to engage in membrane interactions for cell entry during infection but how non-enveloped viruses sense pH is largely undefined. Here, we report the structures — at high and low pH conditions — of bluetongue virus (BTV), which enters cells via a two-stage endosomal process. The receptor-binding protein VP2 possesses a zinc-finger and a conserved His866, which may function to maintain VP2 in a metastable state and to sense early-endosomal pH, respectively. The membrane penetration protein VP5 has three domains: dagger, unfurling, and anchoring. Notably, the β-meander motif of the anchoring domain contains a histidine cluster that could sense the late-endosomal pH and four putative membrane-interaction elements. Exposing BTV to low pH detaches VP2 and dramatically refolds the dagger and unfurling domains of VP5. Our biochemical and structure-guided mutagenesis studies support these coordinated pH-sensing mechanisms.