Expansion of Type II CAAX Proteases Reveals Evolutionary Origin of γ-Secretase Subunit APH-1

Intramembrane proteases are responsible for a number of regulated proteolysis events occurring within or near the plasma and intracellular membranes. Members of one large and diverse family of putative intramembrane metalloproteases are widely distributed in all domains of life, including the type II CAAX prenyl proteases and their prokaryotic homologs with putative bacteriocin-related functions. We used sensitive 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 several 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-1ʹs evolutionary origin and raises the possibility that APH-1 may possess proteolytic activity in the current or ancestral form of γ-secretase.