C‐terminal anchor endolysins—proposing a third class of tailed bacteriophage endolysins

Endolysins-enzymes produced by tailed bacteriophages to degrade bacterial cell walls-have traditionally been classified as canonical or signal-anchor-release (SAR) endolysins. However, analysis of expanding viral (meta)genomic data has revealed a third class, which we designate as C-terminal anchor (CTA) endolysins. These enzymes feature an N-terminal enzymatic domain, a C-terminal transmembrane domain, and typically lack signal sequences, distinguishing them from SAR endolysins. CTA endolysins span all known enzymatic activities and exhibit diverse architectures, though most have a single transmembrane helix and an N-out, C-in topology, consistent with periplasmic activity. While their functional mechanisms remain to be elucidated, our findings suggest that CTA endolysins are nearly as prevalent as SAR endolysins and represent a distinct, previously unrecognized branch of the endolysin world.