Proposed model of PEP-CTERM domain protein processing by EpsH. A) The PEP-CERM domain protein (orange) first is targeted to the inner membrane by its N-terminal signal peptide. Cleavage of the signal peptide by signal peptidase leaves the protein anchored by its C-terminal transmembrane helix. The PEP motif is predicted to lie at the membrane-periplasm interface where it is recognized by and binds to EpsH (green) adjacent to a catalytic triad on its periplasmic surface. Both the PEP-CTERM domain and EpsH are oriented in the membrane by their asymmetrical positive charge distribution (red). The cysteine sulfur nucleophile (purple) cleaves the bound PEP motif at an unspecified location. B) The covalently linked protein is subsequently transferred to an unknown periplasmic nucleophile (blue), likely destined to cross the outer membrane for incorporation into the exopolysaccharide layer.