Sterol regulatory element-binding protein (SREBP) Site-2 protease (S2P), a zinc metalloprotease (MEROPS family M50A), regulates intramembrane proteolysis (RIP) of SREBP and is part of a signal transduction mechanism involved in sterol and lipid metabolism. In sterol-depleted mammalian cells, a two-step proteolytic process releases the N-terminal domains of SREBPs from membranes of the endoplasmic reticulum (ER). These domains translocate into the nucleus, where they activate genes of cholesterol and fatty acid biosynthesis. The first cleavage occurs at Site-1 within the ER lumen to generate an intermediate that is subsequently released from the membrane by cleavage at Site-2, which lies within the first transmembrane domain. It is the second proteolytic step that is carried out by the SREBP Site-2 protease (S2P) which is present in this CD family. This group appears to be limited to eumetazoan proteins and contains one PDZ domain.