Intramembrane proteases are responsible for a number of regulated proteolysis e
vents occurring within or near the plasma and intracellular membranes. Members of one large and di
verse family of putati
ve intramembrane metalloproteases are widely distributed in all domains of life, including the type II CAAX prenyl proteases and their prokaryotic homologs with putati
ve bacteriocin-related functions. We used sensiti
ve sequence similarity searches to expand this large CPBP (CAAX proteases and bacteriocin-processing enzymes) family to include more than 5800 members and infer its homologous relationships to se
veral other protein families, including the PrsW proteases, the DUF2324 (DUF, domain of unknown function) family and the γ-secretase subunit APH-1 proteins. They share four predicted core transmembrane segments and possess similar yet distinct sets of sequence motifs. Remote similarity between APH-1 and membrane proteases sheds light on APH-1's e
volutionary origin and raises the possibility that APH-1 may possess proteolytic acti
vity in the current or ancestral form of γ-secretase.
Research Highlights
► The CPBP intramembrane proteases are widely distributed in all domains of life. ► CPBP, PrsW, DUF2324 and γ-secretase subunit APH-1 are distantly related. ► APH-1 may possess proteolytic activity in the extant or ancestral form of γ-secretase.