Abstract
Among the known intramembrane-cleaving proteases (I-CLiPs), the aspartate proteases are unique. Unlike I-CLiPs of the serine- and metalloprotease-type, which share their respective active site motifs with their classical counterparts, the aspartate protease I-CLiPs acquired a novel characteristic GxGD active site motif during evolution. These so-called GxGD-type proteases include the presenilin (PS), signal peptide peptidase (SPP), SPP-like protease (SPPL) families and the related type IV prepilin peptidase family, bacterial leader peptidases, which share the same active site motif, but which cleave their substrates directly at, rather than within, the membrane. PS, SPP and SPPLs adopt a similar, but inverted membrane topology with respect to their active site orientation. PS is the founding member of the GxGD-type I-CLiPs and has been identified as the catalytic subunit of Γ-secretase. The major function of this protease complex appears to be the clearance of the remnants of a large number of type I membrane proteins that have undergone shedding of their ectodomains. For some substrates of Γ-secretase, most prominently for the cell surface receptor Notch, Γ-secretase cleavage is coupled with signaling by the release of a nuclear-targeted intracellular domain (ICD). In the case of Notch, the ICD functions in the nucleus as a key transcriptional regulator for cell differentiation in development and adulthood. In addition, Γ-secretase is a pivotal enzyme in Alzheimer’s disease (AD), responsible for the liberation of the AD-causing amyloid β-peptide from its precursor protein. SPP and SPPLs exert similar functions, which, however, use type II membrane proteins as substrates consistent with their opposite topologies compared to PS. Thus, the major function of SPP is likely to be to clear the ER membrane of signal peptides of secretory proteins, whereas SPPL2a and b have recently been shown to cleave tumor necrosis factor UPalpha to release an ICD that triggers interleukin-12 signaling. Despite the similarities in their overall biological functions, the major difference is that PS requires partner proteins for its proteolytic function, whereas SPP and probably also the SPPLs do not
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Steiner, H., Haass, C. (2007). GXGD-Type Intramembrane Proteases. In: Hooper, N.M., Lendeckel, U. (eds) Intramembrane-Cleaving Proteases (I-CLiPs). Proteases in Biology and Disease, vol 6. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-6311-4_3
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