Peptidase_A22B
Identifiers
SymbolPeptidase_A22B
PfamPF04258
Pfam clanCL0130
InterProIPR007369
MEROPSA22
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Peptidase_A24
Identifiers
SymbolPeptidase_A24
PfamPF01478
Pfam clanCL0130
InterProIPR000045
MEROPSA24
OPM superfamily244
OPM protein3s0x
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

In molecular biology, the Signal Peptide Peptidase (SPP) is a type of protein that specifically cleaves parts of other proteins. It is an intramembrane aspartyl protease with the conserved active site motifs 'YD' and 'GxGD' in adjacent transmembrane domains (TMDs). Its sequences is highly conserved in different vertebrate species. SPP cleaves remnant signal peptides left behind in membrane by the action of signal peptidase[1] and also plays key roles in immune surveillance and the maturation of certain viral proteins.[2]

Biological function

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.[3]

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.[4]

In mice, a nonamer peptide originating from the SPP protein serves as minor histocompatibility antigen HM13 that plays a role in transplant rejection[5][6]

The homologous proteases SPPL2A and SPPL2B promote the intramembrane cleavage of TNFα in activated dendritic cells and might play an immunomodulatory role.[7][8] For SPPL2c and SPPL3 no substrates are known.

SPPs do not require cofactors as demonstrated by expression in bacteria and purification of a proteolytically active form. The C-terminal region defines the functional domain, which is in itself sufficient for proteolytic activity.[9]

Type IV leader peptidase

Another family of signal aspartic endopeptidases was found in bacteria. Bacteria produce a number of protein precursors that undergo post-translational methylation and proteolysis prior to secretion as active proteins. Type IV prepilin leader peptidases are enzymes that mediate this type of post-translational modification. Type IV pilin is a protein found on the surface of Pseudomonas aeruginosa, Neisseria gonorrhoeae and other Gram-negative pathogens. Pilin subunits attach the infecting organism to the surface of host epithelial cells. They are synthesised as prepilin subunits, which differ from mature pilin by virtue of containing a 6-8 residue leader peptide consisting of charged amino acids. Mature type IV pilins also contain a methylated N-terminal phenylalanine residue.

The bifunctional enzyme prepilin peptidase (PilD) from Pseudomonas aeruginosa is a key determinant in both type-IV pilus biogenesis and extracellular protein secretion, in its roles as a leader peptidase and methyl transferase (MTase). It is responsible for endopeptidic cleavage of the unique leader peptides that characterise type-IV pilin precursors, as well as proteins with homologous leader sequences that are essential components of the general secretion pathway found in a variety of Gram-negative pathogens. Following removal of the leader peptides, the same enzyme is responsible for the second posttranslational modification that characterises the type-IV pilins and their homologues, namely N-methylation of the newly exposed N-terminal amino acid residue.[10]

See also

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. Bibcode:2002Sci...296.2215W. doi:10.1126/science.1070925. PMID 12077416. S2CID 45633906.
  2. ^ Martoglio B, Golde TE (October 2003). "Intramembrane-cleaving aspartic proteases and disease: presenilins, signal peptide peptidase and their homologs". Hum. Mol. Genet. 12 Spec No 2: R201-6. doi:10.1093/hmg/ddg303. hdl:20.500.11850/53541. PMID 12966028.
  3. ^ 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. doi:10.4049/jimmunol.167.11.6441. PMID 11714810.
  4. ^ 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.
  5. ^ 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. S2CID 31345625.
  6. ^ "Entrez Gene: H13 histocompatibility (minor) 13".
  7. ^ 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. S2CID 129089.
  8. ^ 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. S2CID 23712486.
  9. ^ Narayanan S, Sato T, Wolfe MS (July 2007). "A C-terminal region of signal peptide peptidase defines a functional domain for intramembrane aspartic protease catalysis". J. Biol. Chem. 282 (28): 20172–9. doi:10.1074/jbc.M701536200. PMID 17517891.
  10. ^ Lory S, Strom MS (June 1997). "Structure-function relationship of type-IV prepilin peptidase of Pseudomonas aeruginosa--a review". Gene. 192 (1): 117–21. doi:10.1016/S0378-1119(96)00830-X. PMID 9224881.

Further reading

External links

Proteases: aspartate proteases (EC 3.4.23)
Enzymes
More
Categories