9.B.47 The γ-Secretase (γ-Secretase) Family
γ-secretase is an unusual membrane-embedded protease, which cleaves the transmembrane domains (TMDs) of type I membrane proteins, including amyloid-beta precursor protein and Notch receptor. A hydrophilic pore is formed by TMD6 and TMD7 of presenilin 1 (PS1), the catalytic subunit of γ-secretase. TMD8, TMD9 and the C-terminus of PS1, which encompass the conserved PAL motif and the hydrophobic C-terminal tip, are critical for the catalytic activity and the formation of the γ-secretase complex. The amino acid residues around the PAL motif and the extracellular/luminal portion of TMD9 are highly water accessible and located in proximity to the catalytic pore (Sato et al., 2008). Furthermore, the region starting from the luminal end of TMD9 toward the C terminus forms an amphipathic alpha-helix-like structure that extends along the interface between the membrane and the extracellular milieu. Competition analysis using γ-secretase inhibitors revealed that the TMD9 is involved in the initial binding of substrates. TMD9 for the catalytic pore allowing substrate entry, crucial for intramembrane proteolysis by γ-secretase, Aph-1C which shows sequence similarity with most of putative ABC membrane protein of Thermobifida fusca (Q47P80). This is the NCBI Anterior Pharynx defective (Aph-1) family.
γ-Secretase consists of Presenilin (PS) and three indispensable subunits: Nicastrin, Aph-1 and Pen-2. PS forms a hydrophilic catalytic pore structure within the lipid bilayer. Takeo et al. (2012) showed that the hydrophilic pore with an open conformation is formed by PS within an immature γ-secretase complex. The binding of the subunits induces close proximity between transmembrane domains facing the catalytic pore.