| Structural highlights
Function
[S10A8_HUMAN] S100A8 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 and adhesion. 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] [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.[12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28]
Publication Abstract from PubMed
The antimicrobial protein calprotectin (CP), a hetero-oligomer of the S100 family members S100A8 and S100A9, is the only identified mammalian Mn(II)-sequestering protein. Human CP uses Ca(II) ions to tune its Mn(II) affinity at a biologically unprecedented hexahistidine site that forms at the S100A8/S100A9 interface, and the molecular basis for this phenomenon requires elucidation. Herein, we investigate the remarkable Mn(II) coordination chemistry of human CP using X-ray crystallography as well as continuous-wave (CW) and pulse electron paramagnetic resonance (EPR) spectroscopies. An X-ray crystallographic structure of Mn(II)-CP containing one Mn(II), two Ca(II), and two Na(I) ions per CP heterodimer is reported. The CW EPR spectrum of Ca(II)- and Mn(II)-bound CP prepared with a 10:0.9:1 Ca(II):Mn(II):CP ratio is characterized by an unusually low zero-field splitting of 485 MHz (E/D = 0.30) for the S = 5/2 Mn(II) ion, consistent with the high symmetry of the His6 binding site observed crystallographically. Results from electron spin-echo envelope modulation and electron-nuclear double resonance experiments reveal that the six Mn(II)-coordinating histidine residues of Ca(II)- and Mn(II)-bound CP are spectroscopically equivalent. The observed (15)N (I = 1/2) hyperfine couplings (A) arise from two distinct classes of nitrogen atoms: the coordinating epsilon-nitrogen of the imidazole ring of each histidine ligand (A = [3.45, 3.71, 5.91] MHz) and the distal delta-nitrogen (A = [0.11, 0.18, 0.42] MHz). In the absence of Ca(II), the binding affinity of CP for Mn(II) drops by two to three orders of magnitude and coincides with Mn(II) binding at the His6 site as well as other sites. This study demonstrates the role of Ca(II) in enabling high-affinity and specific binding of Mn(II) to the His6 site of human calprotectin.
Manganese Binding Properties of Human Calprotectin under Conditions of High and Low Calcium: X-ray Crystallographic and Advanced Electron Paramagnetic Resonance Spectroscopic Analysis.,Gagnon DM, Brophy MB, Bowman SE, Stich TA, Drennan CL, Britt RD, Nolan EM J Am Chem Soc. 2015 Mar 4;137(8):3004-16. doi: 10.1021/ja512204s. Epub 2015 Feb, 18. PMID:25597447[29]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Gagnon DM, Brophy MB, Bowman SE, Stich TA, Drennan CL, Britt RD, Nolan EM. Manganese Binding Properties of Human Calprotectin under Conditions of High and Low Calcium: X-ray Crystallographic and Advanced Electron Paramagnetic Resonance Spectroscopic Analysis. J Am Chem Soc. 2015 Mar 4;137(8):3004-16. doi: 10.1021/ja512204s. Epub 2015 Feb, 18. PMID:25597447 doi:http://dx.doi.org/10.1021/ja512204s
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