| Structural highlights
Function
[S10A9_HUMAN] S100A9 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response. It can induce neutrophil chemotaxis, adhesion, can increase the bactericidal activity of neutrophils by promoting phagocytosis via activation of SYK, PI3K/AKT, and ERK1/2 and can induce degranulation of neutrophils by a MAPK-dependent mechanism. Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions. The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase. Activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transfering arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX. The extracellular functions involve proinfammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its proinflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration. Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the proinflammatory cascade. Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth. Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3. Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK. Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants. Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
Publication Abstract from PubMed
Human S100A9 (Calgranulin B) is a Ca2+-binding protein, from the S100 family, that often presents as a homodimer in myeloid cells. It becomes an important mediator during inflammation once calcium binds to its EF-hand motifs. Human RAGE protein (receptor for advanced glycation end products) is one of the target-proteins. RAGE binds to a hydrophobic surface on S100A9. Interactions between these proteins trigger signal transduction cascades, promoting cell growth, proliferation, and tumorigenesis. Here, we present the solution structure of mutant S100A9 (C3S) homodimer, determined by multi-dimensional NMR experiments. We further characterize the solution interactions between mS100A9 and the RAGE V domain via NMR spectroscopy. CHAPS is a zwitterionic and non-denaturing molecule widely used for protein solubilizing and stabilization. We found out that CHAPS and RAGE V domain would interact with mS100A9 by using 1H-15N HSQC NMR titrations. Therefore, using the HADDOCK program, we superimpose two binary complex models mS100A9-RAGE V domain and mS100A9-CHAPS and demonstrate that CHAPS molecules could play a crucial role in blocking the interaction between mS100A9 and the RAGE V domain. WST-1 assay results also support the conclusion that CHAPS inhibits the bioactivity of mS100A9. This report will help to inform new drug development against cell proliferation.
Blocking the interaction between S100A9 and RAGE V domain using CHAPS molecule: A novel route to drug development against cell proliferation.,Chang CC, Khan I, Tsai KL, Li H, Yang LW, Chou RH, Yu C Biochim Biophys Acta. 2016 Aug 12;1864(11):1558-1569. doi:, 10.1016/j.bbapap.2016.08.008. PMID:27524699[18]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Miyasaki KT, Bodeau AL, Murthy AR, Lehrer RI. In vitro antimicrobial activity of the human neutrophil cytosolic S-100 protein complex, calprotectin, against Capnocytophaga sputigena. J Dent Res. 1993 Feb;72(2):517-23. PMID:8423249
- ↑ Ryckman C, Vandal K, Rouleau P, Talbot M, Tessier PA. Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. J Immunol. 2003 Mar 15;170(6):3233-42. PMID:12626582
- ↑ Vogl T, Ludwig S, Goebeler M, Strey A, Thorey IS, Reichelt R, Foell D, Gerke V, Manitz MP, Nacken W, Werner S, Sorg C, Roth J. MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes. Blood. 2004 Dec 15;104(13):4260-8. Epub 2004 Aug 26. PMID:15331440 doi:10.1182/blood-2004-02-0446
- ↑ Viemann D, Strey A, Janning A, Jurk K, Klimmek K, Vogl T, Hirono K, Ichida F, Foell D, Kehrel B, Gerke V, Sorg C, Roth J. Myeloid-related proteins 8 and 14 induce a specific inflammatory response in human microvascular endothelial cells. Blood. 2005 Apr 1;105(7):2955-62. Epub 2004 Dec 14. PMID:15598812 doi:10.1182/blood-2004-07-2520
- ↑ Kerkhoff C, Nacken W, Benedyk M, Dagher MC, Sopalla C, Doussiere J. The arachidonic acid-binding protein S100A8/A9 promotes NADPH oxidase activation by interaction with p67phox and Rac-2. FASEB J. 2005 Mar;19(3):467-9. Epub 2005 Jan 10. PMID:15642721 doi:10.1096/fj.04-2377fje
- ↑ Nakatani Y, Yamazaki M, Chazin WJ, Yui S. Regulation of S100A8/A9 (calprotectin) binding to tumor cells by zinc ion and its implication for apoptosis-inducing activity. Mediators Inflamm. 2005 Oct 24;2005(5):280-92. PMID:16258195 doi:10.1155/MI.2005.280
- ↑ Li C, Chen H, Ding F, Zhang Y, Luo A, Wang M, Liu Z. A novel p53 target gene, S100A9, induces p53-dependent cellular apoptosis and mediates the p53 apoptosis pathway. Biochem J. 2009 Aug 13;422(2):363-72. doi: 10.1042/BJ20090465. PMID:19534726 doi:10.1042/BJ20090465
- ↑ Sroussi HY, Kohler GA, Agabian N, Villines D, Palefsky JM. Substitution of methionine 63 or 83 in S100A9 and cysteine 42 in S100A8 abrogate the antifungal activities of S100A8/A9: potential role for oxidative regulation. FEMS Immunol Med Microbiol. 2009 Jan;55(1):55-61. doi:, 10.1111/j.1574-695X.2008.00498.x. Epub 2008 Dec 11. PMID:19087201 doi:10.1111/j.1574-695X.2008.00498.x
- ↑ Champaiboon C, Sappington KJ, Guenther BD, Ross KF, Herzberg MC. Calprotectin S100A9 calcium-binding loops I and II are essential for keratinocyte resistance to bacterial invasion. J Biol Chem. 2009 Mar 13;284(11):7078-90. doi: 10.1074/jbc.M806605200. Epub 2009 , Jan 3. PMID:19122197 doi:10.1074/jbc.M806605200
- ↑ Bjork P, Bjork A, Vogl T, Stenstrom M, Liberg D, Olsson A, Roth J, Ivars F, Leanderson T. Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides. PLoS Biol. 2009 Apr 28;7(4):e97. doi: 10.1371/journal.pbio.1000097. PMID:19402754 doi:10.1371/journal.pbio.1000097
- ↑ Ghavami S, Eshragi M, Ande SR, Chazin WJ, Klonisch T, Halayko AJ, McNeill KD, Hashemi M, Kerkhoff C, Los M. S100A8/A9 induces autophagy and apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes that involves BNIP3. Cell Res. 2010 Mar;20(3):314-31. doi: 10.1038/cr.2009.129. Epub 2009 Nov 24. PMID:19935772 doi:10.1038/cr.2009.129
- ↑ Simard JC, Girard D, Tessier PA. Induction of neutrophil degranulation by S100A9 via a MAPK-dependent mechanism. J Leukoc Biol. 2010 May;87(5):905-14. doi: 10.1189/jlb.1009676. PMID:20103766 doi:10.1189/jlb.1009676
- ↑ Simard JC, Simon MM, Tessier PA, Girard D. Damage-associated molecular pattern S100A9 increases bactericidal activity of human neutrophils by enhancing phagocytosis. J Immunol. 2011 Mar 15;186(6):3622-31. doi: 10.4049/jimmunol.1002956. Epub 2011, Feb 16. PMID:21325622 doi:10.4049/jimmunol.1002956
- ↑ Riva M, Kallberg E, Bjork P, Hancz D, Vogl T, Roth J, Ivars F, Leanderson T. Induction of nuclear factor-kappaB responses by the S100A9 protein is Toll-like receptor-4-dependent. Immunology. 2012 Oct;137(2):172-82. doi: 10.1111/j.1365-2567.2012.03619.x. PMID:22804476 doi:10.1111/j.1365-2567.2012.03619.x
- ↑ Koike A, Arai S, Yamada S, Nagae A, Saita N, Itoh H, Uemoto S, Totani M, Ikemoto M. Dynamic mobility of immunological cells expressing S100A8 and S100A9 in vivo: a variety of functional roles of the two proteins as regulators in acute inflammatory reaction. Inflammation. 2012 Apr;35(2):409-19. doi: 10.1007/s10753-011-9330-8. PMID:21487906 doi:10.1007/s10753-011-9330-8
- ↑ Berthier S, Nguyen MV, Baillet A, Hograindleur MA, Paclet MH, Polack B, Morel F. Molecular interface of S100A8 with cytochrome b558 and NADPH oxidase activation. PLoS One. 2012;7(7):e40277. doi: 10.1371/journal.pone.0040277. Epub 2012 Jul 10. PMID:22808130 doi:10.1371/journal.pone.0040277
- ↑ Atallah M, Krispin A, Trahtemberg U, Ben-Hamron S, Grau A, Verbovetski I, Mevorach D. Constitutive neutrophil apoptosis: regulation by cell concentration via S100 A8/9 and the MEK-ERK pathway. PLoS One. 2012;7(2):e29333. doi: 10.1371/journal.pone.0029333. Epub 2012 Feb 17. PMID:22363402 doi:10.1371/journal.pone.0029333
- ↑ Chang CC, Khan I, Tsai KL, Li H, Yang LW, Chou RH, Yu C. Blocking the interaction between S100A9 and RAGE V domain using CHAPS molecule: A novel route to drug development against cell proliferation. Biochim Biophys Acta. 2016 Aug 12;1864(11):1558-1569. doi:, 10.1016/j.bbapap.2016.08.008. PMID:27524699 doi:http://dx.doi.org/10.1016/j.bbapap.2016.08.008
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