Biology:Staphopain A (Staphylococcus aureus)
| Staphopain A | |||||||||
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| Identifiers | |||||||||
| EC number | 3.4.22.48 | ||||||||
| CAS number | 347841-89-8 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
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Staphopain A (EC 3.4.22.48, ScpA, ScpAaur, staphylopain A, staphylococcal cysteine proteinase) is a secreted cysteine protease produced by Staphylococcus aureus. It was first identified in the S. aureus V8 strain as a papain-like cysteine protease. The protease distinguishes itself from the other major proteases of S. aureus in its very broad specificity and its ability to degrade elastin.[1][2]
Genetics
Staphopain A expressed from the gene scpA within the scp operon. The operon also contains the gene scpB for staphostatin A (specific inhibitor of staphopain A), downstream of scpA.[3][4]
Staphopain A is largely co-expressed with the other three major proteases of S. aureus: aureolysin, glutamyl endopeptidase, and staphopain B. The transcription of scp occurs via a promoter controlled by "housekeeping" sigma factor σA and up-regulated by accessory gene regulator agr. It is at also repressed by staphylococcal accessory regulator sarA and by alternative sigma factor σB (a stress response modulator of Gram-positive bacteria). ssp expression is highly expressed in post-exponential growth phase.[4] A more complex network of modulators and of environmental conditions affecting ssp expression have been suggested, however. Up-regulation of aureolysin during phagocytosis have also been observed.[5][6]
The scpA gene has a high prevalence in the genome of both commensal- and pathogenic-type S. aureus strains.[7]
Activation & inhibition
Staphopain A is expressed as an inactive zymogen. In contrast to the other proteases, however, it appears to undergo rapid autocatalytic activation. It is thus also independent of the activation cascade of the three other proteases.[4][8]
S. aureus expresses the intracellular inhibitor staphostatin A, specific against staphopain A. As the activation of staphopain A could occur before it has been secreted by the bacteria, the staphostatin acts as prevention against harmful intracellular activity of the protease.[3][8][9]
Function
Staphopain A is elastinolytic to a degree fairly equal to that of neutrophil elastase, and has a very broad specificity proteolysis.[1][2][10]
Staphopain A is inhibited by phosphorylated cystatin α and α2-macroglobulin.[1][2]
Staphopain A can cleave and lower the activity α1-antitrypsin,[1][2] and inactivate several complement system components.[11]
Biological significance
Staphopain A was shown to inhibit activation of the complement system activation by cleaving components that are part of all three pathways (the classical, alternative, and lectin pathways) of activation. It shows a duplex role in affecting chemotaxis; while inactivating neutrophil CXCR2 receptor, generates an active C5a fragment of C5 (although inactivating C5b).[11][12] However, it has yet to prove any significant impact on the outcome of infection. Inhibition of staphopain A by phosphorylated cystatin α did prevent colony formation in skin tissue, but the effect could also be attributed to staphopain B. Mutation of scpA did not show any impact on the outcome of a skin abscess nor a septic arthritis model.[4][13][14][15] Overlapping activity with the other proteases, plus the complexity of virulence determinants and the infection site environment makes it difficult to determine the impact of the protease in pathogenesis.[1][2]
The elastinolytic properties of the protease could assist in spread of bacteria and also symptomatically to connective tissue destruction.[1][2][10]
Staphopain A participates in S. aureus self-regulatory events, by altering the phenotype of the bacteria via cleavage of surface proteins and by preventing biofilm formation.[1][16]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Kantyka, Tomasz; Shaw, Lindsey N.; Potempa, Jan (January 2013). Rawlings, Neil D.. ed. Handbook of Proteolytic Enzymes. Academic Press. pp. 2150–2157. doi:10.1016/b978-0-12-382219-2.00483-x. ISBN 9780123822192.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "Extracellular proteases of Staphylococcus spp". Biological Chemistry 383 (7-8): 1075–86. July 2002. doi:10.1515/BC.2002.116. PMID 12437090.
- ↑ 3.0 3.1 "The Staphostatin-staphopain complex: a forward binding inhibitor in complex with its target cysteine protease". The Journal of Biological Chemistry 278 (42): 40959–66. October 2003. doi:10.1074/jbc.M302926200. PMID 12874290.
- ↑ 4.0 4.1 4.2 4.3 "The role and regulation of the extracellular proteases of Staphylococcus aureus". Microbiology 150 (Pt 1): 217–28. January 2004. doi:10.1099/mic.0.26634-0. PMID 14702415.
- ↑ "Coordinated and differential control of aureolysin (aur) and serine protease (sspA) transcription in Staphylococcus aureus by sarA, rot and agr (RNAIII)". International Journal of Medical Microbiology 296 (6): 365–80. October 2006. doi:10.1016/j.ijmm.2006.02.019. PMID 16782403.
- ↑ "Interactive regulatory pathways control virulence determinant production and stability in response to environmental conditions in Staphylococcus aureus". Molecular & General Genetics 262 (2): 323–31. September 1999. doi:10.1007/s004380051090. PMID 10517329.
- ↑ "Prevalence of genes encoding extracellular proteases in Staphylococcus aureus - important targets triggering immune response in vivo". FEMS Immunology and Medical Microbiology 66 (2): 220–9. November 2012. doi:10.1111/j.1574-695X.2012.01005.x. PMID 22762789.
- ↑ 8.0 8.1 "Comparison of Staphopain A (ScpA) and B (SspB) precursor activation mechanisms reveals unique secretion kinetics of proSspB (Staphopain B), and a different interaction with its cognate Staphostatin, SspC". Molecular Microbiology 75 (1): 161–77. January 2010. doi:10.1111/j.1365-2958.2009.06974.x. PMID 19943908.
- ↑ "Defense against own arms: staphylococcal cysteine proteases and their inhibitors". Acta Biochimica Polonica 50 (3): 715–24. January 2003. PMID 14515151. http://www.actabp.pl/pdf/3_2003/715.pdf.
- ↑ 10.0 10.1 "Degradation of elastin by a cysteine proteinase from Staphylococcus aureus". The Journal of Biological Chemistry 263 (6): 2664–7. February 1988. PMID 3422637.
- ↑ 11.0 11.1 "Staphylococcal proteases aid in evasion of the human complement system". Journal of Innate Immunity 6 (1): 31–46. January 2014. doi:10.1159/000351458. PMID 23838186.
- ↑ "Staphylococcus aureus Staphopain A inhibits CXCR2-dependent neutrophil activation and chemotaxis". The EMBO Journal 31 (17): 3607–19. August 2012. doi:10.1038/emboj.2012.212. PMID 22850671.
- ↑ "Inhibition of cysteine protease and growth of Staphylococcus aureus V8 and poliovirus by phosphorylated cystatin alpha conjugate of skin". BioFactors 10 (4): 339–45. January 1999. doi:10.1002/biof.5520100404. PMID 10619701.
- ↑ "Synthesis and antibacterial properties of peptidyl derivatives and cyclopeptides structurally based upon the inhibitory centre of human cystatin C. Dissociation of antiproteolytic and antibacterial effects". APMIS 108 (7-8): 473–81. July 2000. doi:10.1034/j.1600-0463.2000.d01-85.x. PMID 11167542.
- ↑ "Impact of staphylococcal protease expression on the outcome of infectious arthritis". Microbes and Infection 6 (2): 202–6. February 2004. doi:10.1016/j.micinf.2003.10.015. PMID 14998519.
- ↑ "Staphopains modulate Staphylococcus aureus biofilm integrity". Infection and Immunity 81 (9): 3227–38. September 2013. doi:10.1128/IAI.00377-13. PMID 23798534.
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