Structural diversification of phage tail fibers...

Structural diversification of phage tail fibers enables recognition of diverse type IV pili

Abstract

Viruses must recognize receptors on host surfaces to initiate infection, but these receptors can evolve rapidly, posing a fundamental challenge to viral persistence. The type IV pilus of Pseudomonas aeruginosa is an ideal model system to study virus–receptor coevolution because its major pilin subunit PilA exhibits extensive sequence and chemical diversity while remaining essential for bacteriophage (phage) attachment. Here, we combined comparative genomics with structural and functional analyses to determine how pilus-dependent phages maintain infectivity despite extensive receptor diversification. Pilin variation was concentrated at solvent-exposed regions, altering filament surface chemistry while preserving key subunit–subunit interfaces required for pilus assembly. Despite this variation, phages recognized divergent pilins more effectively than polyclonal antisera. However, phages differed markedly in their sensitivity to receptor perturbation: some required electrostatic and structural compatibility, whereas others tolerated substantial receptor variation, including posttranslational glycosylation. Comparisons of AlphaFold3 models revealed two structurally distinct classes of tail fiber architecture associated with those phenotypes. Phages encoding tail fibers with structurally and sequence-conserved C-terminal domains were more sensitive to receptor perturbation, while those encoding structurally conserved but sequence-diverse C-terminal domains infected strains expressing highly divergent pilins. Together, these findings suggest that modular diversification of tail fibers provides a structural route by which phages accommodate receptor evolution.