The internal capsid protein VI mediates adenovirus (AdV) endosome penetration during cell entry. Essential to this process is the release of protein VI from the AdV capsid and subsequent membrane targeting and insertion by the liberated VI molecules within the endocytic vesicle. In this study, we describe a human AdV (HAdV) substitution mutant (AdV VI-G48C) within the critical N-terminal amphipathic α-helical domain of protein VI. The VI-G48C virus displays altered capsid stability that impacts protein VI release, membrane disruption and virus infectivity. This is due in part to aberrant disulfide-bonding of protein VI molecules within the AdV particle. Our results provide insight into the structural organization of protein VI in the virus particle, as well as highlight the role of protein VI in cell entry.
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