Signal peptidase peptide

Novel PS-related famihes of proteins (IMPAS/PSH/signal peptide peptidases [SPSs]) have been identified (163). Intramembrane protease-associated or intramembrane protease aspartic protein Impas 1 (1MP1)/SPS induces intramembranous cleavage of PSl holoprotein in cultured cells coexpressing these proteins. Mutations in evolutionary invariant sites in hlMPl or specific y-secretase inhibitors abolish the hlMPl-mediated endoproteolysis of PSl. In contrast, AD-like mutations in neither hlMPl nor PSl substrate abridge the PSl cleavage (163). 

Weihofen, A., Lemberg, M.K., Friedmann, E., et al. (2003) Targeting presenilin-type aspartic protease signal peptide peptidase with y-secretase inhibitors. J. Biol. Chem., 278, 16528-16533. 

Figure 8 Comparison of signal peptide peptidase (SPP) with presenilin and the y-secretase complex. Signal peptides are removed from membrane proteins via signal peptidase (SP), and these peptides are released from the membrane by SPP-mediated intramembrane proteolysis. SPP, like presenilin, contains two aspartates that are essential for protease activity, but the conserved aspartate-containing motifs are in the opposite orientation compared with their presenilin counterparts. Consistent with the flipped orientation of SPP vis-a-vis presenilin, the substrates of these two proteases also run in the opposite direction. Unlike presenilin, SPP apparently does not require other protein cofactors or cleavage into two subunits for proteolytic activity.

Sato T, Nyborg AC, Iwata N, Diehl TS, Saido TC, Golde TE, Wolfe MS. Signal peptide peptidase biochemical properties and modulation by nonsteroidal anti-inflammatory drugs. Biochemistry. In Press. 

Weihofen A, Binns K, Lemberg MK, Ashman K, MartogUo B. Identification of signal peptide peptidase, a preseniUn-type aspartic protease. Science 2002 296 2215-2218. 

Nyborg AC, Kornilova AY, Jansen K, Ladd TB, Wolfe MS, Golde TE. Signal peptide peptidase forms a homodimer that is labeled by an active site directed y-secretase inhibitor. J. Biol. Chem. 2004 5 5. 

Lemberg MK, Martoglio B. Requirements for signal peptide peptidase-catalyzed intramembrane proteolysis. Mol. Cell 2002 10 735-744. 

Step 7. During or after translation, signal peptidase removes the signal sequence. Signal peptide peptidase digests the signal sequence after cleavage. 

The signal hypothesis postulates the existence of several proteins necessary for secretion. These include the components of the SRP, which is proposed to bind to the signal sequence and block further translation of the mRNA coding for the mature protein SRP receptor, or docking protein, which relieves the translation block imposed by the SRP ribophorins, which bind the ribosome to the ER membrane signal peptidase and signal-peptide peptidase, discussed above and other proteins, which form a pore or transport apparatus in the membrane. Some of these proteins, the SRP, SRP receptor, signal peptidase, and ribophorins, have been isolated from eukaryotic cell extracts and characterized. 

Kocabiyik, S., Demirok, B. Cloning and overexpression of a thermostable signal peptide peptidase (SppA) from Thermoplasma volcanium GSSl in E. coli. Biotechnol J 2009, 4(7), 1055-1065. 

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