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γ-secretase

The presenilin 1 (PS1) and presenilin 2 (PS2) proteins that form the catalytic core of the γ- secretase protease complex were initially discovered in genetic screens for mutations causing early onset forms of familial Alzheimer’s disease (FAD). γ-Secretase is a multi-subunit transmembrane proteolytic complex belonging to the family of intramembrane cleaving proteases (ICliPs) of which there are four classes; the serine proteases of the Rhomboid class, the metalloproteases in the Site-2-proteases (S2P) class and the GXGD aspartyl proteases, signal peptide peptidases (SPP) and γ-secretase. Of all the ICliPs studied to date γ- secretase is unique as it is a four-protein complex, consisting of the presenilins, anterior pharynx-defective 1 (Aph-1), presenilin enhancer 2 (Pen-2) and Nicastrin, which is only found in multicellular organisms. 
In humans, two forms of presenilin (PS1 and PS2) and two forms of Aph-1 have been identified, one of the Aph-1 homologs is also expressed in two isoforms via alternative splicing, leading to the possible existence of at least six different γ-secretase complexes that may have tissue- or cell type specificity.  To date more than 90 γ-secretase substrates have been identified including APP and a large number of cell surface receptors and adhesion molecules such as Notch, ErbB4, CD44 and E-cadherin. In general substrates that undergo regulated intramembrane proteolysis are initially cleaved in the extracellular domain by sheddases such as TACE (TNFα converting enzyme) or ADAM (a disintegrin and metalloproteinase domain)/α-secretase, or by aspartyl proteases, such as BACE/β-secretase, before cleavage by the I-CLiP family of proteases. Beyond their role in γ-secretase protease complexes, it has been proposed and in some cases demonstrated that the presenilins have many highly conserved γ-secretase independent regulatory functions in cellular processes and cell signalling, including Wnt signalling, endoplasmic reticulum (ER) calcium homeostasis, as well as lysosomal function and autophagy.1.Duggan SP,et al. Cell Signal. 2016;28(1):1–11.

References

1.Duggan SP,et al. Cell Signal. 2016;28(1):1–11.