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Significance To achieve their full infectious potential, virus particles transition from relatively inert to highly reactive agents upon encountering an appropriate host cell. Here we examine the basis for this transition in adenovirus, a human pathogen and widely used gene-transfer vector. Adenovirus particles contain more than 10 different proteins plus the viral genome. We focus on the interplay between two of these proteins: The major core protein VII, involved in genome condensation, and the internal minor coat protein VI, bearing lytic activity required to rupture endosomes during entry. Our data support a model where the ability of protein VII to compete with VI in hexon binding facilitates proper exposure of the lytic peptide, ensuring virion escape from the early endosome.

Dynamic competition for hexon binding between core protein VII and lytic protein VI promotes adenovirus maturation and entry