3q70

Structural highlights

Function

CARP2_CANAX Secreted aspartic peptidases (SAPs) are a group of ten acidic hydrolases considered as key virulence factors (PubMed:11478679, PubMed:12761103, PubMed:15820985, PubMed:15845479, PubMed:19880183, PubMed:20713630, PubMed:22302440, PubMed:23927842). These enzymes supply the fungus with nutrient amino acids as well as are able to degrade the selected host's proteins involved in the immune defense (PubMed:11478679, PubMed:12761103, PubMed:15820985, PubMed:15845479, PubMed:19880183, PubMed:20713630, PubMed:22302440, PubMed:23927842). Induces host inflammatory cytokine production in a proteolytic activity-independent way (PubMed:20713630). Plays a role in tissue damage during superficial infection (PubMed:12761103). Moreover, acts toward human hemoglobin though limited proteolysis to generate a variety of antimicrobial hemocidins, enabling to compete with the other microorganisms of the same physiological niche using the microbicidal peptides generated from the host protein (PubMed:23927842).^{[1] [2] [3] [4] [5] [6] [7] [8]} Plays a key role in defense against host by cleaving histatin-5 (Hst 5), a peptide from human saliva that carries out fungicidal activity (PubMed:27390786, PubMed:29143452, PubMed:31675138). The cleavage rate decreases in an order of SAP2 > SAP9 > SAP3 > SAP7 > SAP4 > SAP1 > SAP8 (PubMed:27390786). The first cleavage occurs between residues 'Lys-17' and 'His-18' of Hst 5, giving DSHAKRHHGYKRKFHEK and HHSHRGY peptides (PubMed:27390786). Simultaneously, the DSHAKRHHGYKRK peptide is also formed (PubMed:27390786). Further fragmentation by SAP2 results in FHEK and DSHAKRHHGY products (PubMed:27390786).^{[9] [10] [11]}

References

1. ↑ Schaller M, Januschke E, Schackert C, Woerle B, Korting HC. Different isoforms of secreted aspartyl proteinases (Sap) are expressed by Candida albicans during oral and cutaneous candidosis in vivo. J Med Microbiol. 2001 Aug;50(8):743-7. PMID:11478679
2. ↑ Schaller M, Bein M, Korting HC, Baur S, Hamm G, Monod M, Beinhauer S, Hube B. The secreted aspartyl proteinases Sap1 and Sap2 cause tissue damage in an in vitro model of vaginal candidiasis based on reconstituted human vaginal epithelium. Infect Immun. 2003 Jun;71(6):3227-34. PMID:12761103 doi:10.1128/IAI.71.6.3227-3234.2003
3. ↑ Copping VM, Barelle CJ, Hube B, Gow NA, Brown AJ, Odds FC. Exposure of Candida albicans to antifungal agents affects expression of SAP2 and SAP9 secreted proteinase genes. J Antimicrob Chemother. 2005 May;55(5):645-54. PMID:15820985 doi:10.1093/jac/dki088
4. ↑ Schaller M, Korting HC, Borelli C, Hamm G, Hube B. Candida albicans-secreted aspartic proteinases modify the epithelial cytokine response in an in vitro model of vaginal candidiasis. Infect Immun. 2005 May;73(5):2758-65. PMID:15845479 doi:10.1128/IAI.73.5.2758-2765.2005
5. ↑ Gropp K, Schild L, Schindler S, Hube B, Zipfel PF, Skerka C. The yeast Candida albicans evades human complement attack by secretion of aspartic proteases. Mol Immunol. 2009 Dec;47(2-3):465-75. PMID:19880183 doi:10.1016/j.molimm.2009.08.019
6. ↑ Pietrella D, Rachini A, Pandey N, Schild L, Netea M, Bistoni F, Hube B, Vecchiarelli A. The Inflammatory response induced by aspartic proteases of Candida albicans is independent of proteolytic activity. Infect Immun. 2010 Nov;78(11):4754-62. PMID:20713630 doi:10.1128/IAI.00789-10
7. ↑ Ramage G, Coco B, Sherry L, Bagg J, Lappin DF. In vitro Candida albicans biofilm induced proteinase activity and SAP8 expression correlates with in vivo denture stomatitis severity. Mycopathologia. 2012 Jul;174(1):11-19. PMID:22302440 doi:10.1007/s11046-012-9522-2
8. ↑ Bochenska O, Rapala-Kozik M, Wolak N, Bras G, Kozik A, Dubin A, Aoki W, Ueda M, Mak P. Secreted aspartic peptidases of Candida albicans liberate bactericidal hemocidins from human hemoglobin. Peptides. 2013 Oct;48:49-58. doi: 10.1016/j.peptides.2013.07.023. Epub 2013 Aug, 6. PMID:23927842 doi:http://dx.doi.org/10.1016/j.peptides.2013.07.023
9. ↑ Bochenska O, Rapala-Kozik M, Wolak N, Aoki W, Ueda M, Kozik A. The action of ten secreted aspartic proteases of pathogenic yeast Candida albicans on major human salivary antimicrobial peptide, histatin 5. Acta Biochim Pol. 2016;63(3):403-10. PMID:27390786 doi:10.18388/abp.2016_1318
10. ↑ Ikonomova SP, Moghaddam-Taaheri P, Jabra-Rizk MA, Wang Y, Karlsson AJ. Engineering improved variants of the antifungal peptide histatin 5 with reduced susceptibility to Candida albicans secreted aspartic proteases and enhanced antimicrobial potency. FEBS J. 2018 Jan;285(1):146-159. PMID:29143452 doi:10.1111/febs.14327
11. ↑ Ikonomova SP, Moghaddam-Taaheri P, Wang Y, Doolin MT, Stroka KM, Hube B, Karlsson AJ. Effects of histatin 5 modifications on antifungal activity and kinetics of proteolysis. Protein Sci. 2020 Feb;29(2):480-493. PMID:31675138 doi:10.1002/pro.3767