Rhomboid proteins exist in three topological forms. The smallest, catalytically active form of a rhomboid protease consists of a 6TM core, with variable amino termini (dashed lines). Most eukaryotic and mitochondrial rhomboid proteases have an additional TM segment, added either carboxy-terminally (eukaryotes, blue) or amino-terminally (mitochondria, red) to the 6TM core, as depicted. Catalytic residues are in yellow for nucleophilic chemistry (hydrolysis) and white for electrophilic residues (oxyanion transition state stabilization). Cytoplasm is down in each diagram.