Signal peptide peptidase

The Signal Peptide Peptidase (SPP) is an intramembrane aspartyl protease with the conserved active site motifs 'YD' and 'GxGD' in in adjacent transmembrane domains (TMDs). Its sequences is highly conserved in different vertebrate species. Its substrates are signal peptides, which upon cleavage by Signal Peptidase span the ER membrane similar to a type II transmembrane protein.[1]

Physiologically SPP processes signal peptides of classical MHC class I preproteins. A nine amino acid-long cleavage fragment is then presented on HLA-E receptors and modulates the activity of natural killer cells.[2]

SPP also plays a pathophysiological role; it cleaves the structural nucleocapsid protein (also known as core protein) of the Hepatitis C virus and thus influences viral reproduction rate.[3]

In mice, a nonamer peptide originating from the SPP protein serves as minor histocompatibility antigen HM13 that plays a role in transplant rejection[4][5]

The homologous proteases SPPL2A and SPPL2B promote the intramembrane cleavage of TNFα in activated dendritic cells and might play an immunomodulatory role.[6][7] For SPPL2c and SPPL3 no substrates are known.

References

  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, Mori Y, Komoda Y, Okamoto T, Okochi M, Takeda M, Suzuki T, Moriishi K, Matsuura Y (2008). "Intramembrane processing by signal peptide peptidase regulates the membrane localization of hepatitis C virus core protein and viral propagation". J. Virol. 82 (17): 8349–61. doi:10.1128/JVI.00306-08. PMC 2519675. PMID 18562515. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2519675. 
  4. ^ Snell GD, Cudkowicz G, Bunker HP (Jun 1967). "Histocompatibility genes of mice. VII. H-13, a new histocompatibility locus in the fifth linkage group". Transplantation 5 (3): 492–503. doi:10.1097/00007890-196705000-00011. PMID 5340356. 
  5. ^ "Entrez Gene: H13 histocompatibility (minor) 13". http://www.ncbi.nlm.nih.gov/gene/14950. 
  6. ^ Friedmann E, Hauben E, Maylandt K, et al. (2006). "SPPL2a and SPPL2b promote intramembrane proteolysis of TNFα in activated dendritic cells to trigger IL-12 production". Nat. Cell Biol. 8 (8): 843–8. doi:10.1038/ncb1440. PMID 16829952. 
  7. ^ 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

External links

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Pepsin · Chymosin · Renin · Signal peptide peptidase · Beta secretase (1, 2)
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