Hypothetical model of the role of PS in Notch and APP processing. The diagram shows the predicted eight–TM domain topology of PS, which occurs principally as a cleaved heterodimer. Some Notch and APP molecules form complexes with PS. Two aspartate residues (D) in TM6 and TM7 of PS are required for the cleavages of Notch and APP within their TM domains, and these are predicted to align with the respective sites of cleavage in the two substrates. It is likely that PS directly effects these cleavages, as part of a multi-protein complex (i.e.,γ-secretase). PS-mediated proteolysis of both Notch and APP is preceded by ectodomain shedding mediated by certain ADAM proteases. Alternatively, a subset of APP holoproteins can undergo ectodomain shedding by β-secretase. Several motifs are depicted in Notch: EGF-like repeats (yellow circles), LNG repeats (red diamonds), a single TM (orange box), the RAM23 domain (blue square), a nuclear localization sequence (red rectangle), and six cdc10/ankyrin repeats (green ovals). Following the putative intramembranous cleavage mediated by PS, the Notch intracellular domain is released to the nucleus to activate transcription of target genes. APP contains the Aβ region (light blue box), which is released into the lumen after sequential cleavages of APP by β-secretase and then γ-secretase/PS. Some of the AICD reaches the nucleus as well.