A hypothetical scenario for the origin and dissemination of the rhomboid family proteases. The figure schematically shows the proposed three stages of evolution of the rhomboid family. In (a), the progenitor of the rhomboid family functions as a transporter for a regulatory peptide in some bacterial lineage. In (b), the catalytic site of the intramembrane protease evolves, allowing the switch to RIP as the mechanism of the regulatory peptide release. In (c), the emergence of RIP is followed by a burst of HGT. R, regulatory peptide. The transmembrane helices of rhomboid are designated as in Figure 1; their topology in the membrane is based on that proposed in . The catalytic histidine and serine are shown and connected by a dotted line to indicate the proposed charge-relay system of the protease; possible ancillary catalytic residues are not shown.