Structural and functional similarities/differences between SPP and γ-secretase. SPP and γ-secretase are similar in that they are both multipass transmembrane enzymes that share the YD/GXGD catalytic motif and cleave their respective substrates in the transmembrane region. SPP and PS, the catalytic subunit of γ-secretase, both transverse the membrane 9 times. The differences between the enzymes include their limited sequence homology, their inverse orientation in the membrane, and their specificity for either type 1 or type 2 substrates. Additionally, SPP functions without protein cofactors while PS requires at least 3 additional proteins (Aph1, Nct, and Pen2) for γ-secretase activity.