Signal peptide peptidase

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The Signal Peptide Peptidase (SPP) and its homologs (SPPL2a/b/c, SPPL3) are a class of transmembrane aspartyl proteases with the conserved motives YD ... GxGD ...PALL. Their sequences are highly conserved in different vertebrate species. Their substrates are Type II transmembrane proteins.[1]

Physiologically SPP processes signal peptides of HLA preproteins. A 9 AS cleavage fragment is then presented on HLA-E receptors and modulates the activity of natural killer cells.[2]

SPP also plays a pathophysiolocigal role; it cleaves the core protein of Hepatitis C virus and thus influences the reproduction rate of HCV.[3]

SPPL2a/b promotes the intramembrane cleavage of TNFα in activated dendritic cells and might play an immunomodulatory role.[4][5]


  1. Weihofen A, Binns K, Lemberg MK, Ashman K, Martoglio B (2002). "Identification of signal peptide peptidase, a presenilin-type aspartic protease". Science. 296 (5576): 2215–8. doi:10.1126/science.1070925. PMID 12077416.
  2. Lemberg MK, Bland FA, Weihofen A, Braud VM, Martoglio B (2001). "Intramembrane proteolysis of signal peptides: an essential step in the generation of HLA-E epitopes". J. Immunol. 167 (11): 6441–6. PMID 11714810.
  3. Okamoto K, Moriishi K, Miyamura T, Matsuura Y (2004). "Intramembrane proteolysis and endoplasmic reticulum retention of hepatitis C virus core protein". J. Virol. 78 (12): 6370–80. doi:10.1128/JVI.78.12.6370-6380.2004. PMID 15163730.
  4. Friedmann E, Hauben E, Maylandt K; et al. (2006). "SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production". Nat. Cell Biol. 8 (8): 843–8. doi:10.1038/ncb1440. PMID 16829952.
  5. Fluhrer R, Grammer G, Israel L; et al. (2006). "A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD aspartyl protease SPPL2b". Nat. Cell Biol. 8 (8): 894–6. doi:10.1038/ncb1450. PMID 16829951.

Further reading

  • Paetzel M, Karla A, Strynadka NC, Dalbey RE (2002). "Signal peptidases". Chem. Rev. 102 (12): 4549–80. PMID 12475201.

External links