Biology:Calprotectin

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Calprotectin is a complex of the mammalian proteins S100A8 and S100A9.[1][2][3] Other names for calprotectin include MRP8-MRP14, calgranulin A and B, cystic fibrosis antigen, L1, 60BB antigen, and 27E10 antigen.[2][4] The proteins exist as homodimers but preferentially exist as S100A8/A9 heterodimers or heterotetramers (calprotectin) with antimicrobial, proinflammatory and prothrombotic properties.[5][6] In the presence of calcium, calprotectin is capable of sequestering the transition metals iron,[7] manganese and zinc[2][8] via chelation.[9] This metal sequestration affords the complex antimicrobial properties.[2][8] Calprotectin is the only known antimicrobial manganese sequestration protein complex.[10] Calprotectin comprises as much as 60% of the soluble protein content of the cytosol of a neutrophil,[2][11][12] and it is secreted by an unknown mechanism during inflammation.[4] Faecal calprotectin has been used to detect intestinal inflammation (colitis or enteritis) and can serve as a biomarker for inflammatory bowel diseases.[11][13] Blood-based calprotectin (in serum and plasma) is used in diagnostics of multiple inflammatory diseases, including autoimmune diseases, like arthritis, and severe infections including sepsis.[14][15]

Structure

Crystal structure of Mn2+ and Ca2+ loaded calprotectin, showing two S100A8-S100A9 dimers. The grey and blue chains represent S100A8 and S100A9, respectively. Purple spheres represent Mn2+ and green spheres represent Ca2+. Only one manganese ion can bind per calprotectin dimer.

The human homologue of calprotectin is a 24 kDa dimer,[10] and is formed by the protein monomers S100A8 (10,835 Da) and S100A9 (13,242 Da).[5][6] The primary structure of calprotectin can vary between species. For instance, the mouse homologue of S100A8 is 10,295 Da,[16] while the S100A9 homologue is 13,049 Da.[17] Early size exclusion chromatography experiments incorrectly indicated that calprotectin had a molecular mass of 36.5 kDa;[2][12] occasionally this value is used in contemporary literature. Calprotectin S100A8-S100A9 dimers can non-covalently pair with one another to form 48 kDa tetramers.

Metal binding

Calprotectin has a high affinity for calcium, zinc, iron, and manganese.[11][12][18][7] Each of S100A8 and S100A9 contain two EF-hand type Ca2+ binding sites,[10][4] and calprotectin is able to bind a total of four calcium ions per dimer or eight calcium ions per tetramer.[19] Calcium binding induces a conformational change in the complex that improves its affinity for transition metals, and promotes tetramer formation.[2][10] A maximum of two transition metal ions may bind to each calprotectin S100A8-S100A9 dimer.[10]

A calprotectin dimer can bind only one manganese or iron ion with high affinity, and it can do this only in the presence of calcium.[10][20][7] Zinc can bind at two sites within the calprotectin dimer, and this can occur in the absence of calcium.[2] Calcium, however, improves calprotectin's affinity for zinc.[10] While calprotectin metal binding occurs at the interface of S100A9 and S100A8 monomers, the independent monomers have some capacity for zinc binding, and may contribute to zinc homeostasis within mammals.[2][5][6]

His6 coordination of Mn2+ in calprotectin. S100A8 histidine residues are coloured grey, S100A9 histidine residues are coloured purple.

The first of the two calprotectin metal binding sites consists of a His3Asp motif, with S100A8 contributing two histidine ligands (His83 and His87), and S100A9 contributing a histidine and an aspartic acid ligand (His20 and Asp30).[10] The second site can coordinate metals through a tetra-histidine (His4) or a hexa-histidine (His6) binding motif. In the case of His4 binding, S100A8 coordinates through both His17 and His27 while S100A9 coordinates through His91 and His95.[10] In hexa-histidine binding two further histidine residues, His103 and His105, are recruited from the C-terminal end of S100A9 to enable octahedral coordination of the transition metal.[10] Manganese or iron are bound by the calprotectin dimer at this His6 site.[10][7] Zinc can be bound to either of the sites that form at the interface between S100A8 and S100A9 monomers.[10][20]

Inflammatory disease

Calprotectin constitutes up to 60% of soluble protein content in the cytosol of neutrophil granulocytes,[2][11][12] and it can be found at a lower concentration in monocytes, macrophages, and squamous epithelial cells.[2][11][12] Calprotectin enters into pus and abscess fluid during neutrophil cell death, along with other antimicrobial proteins.[2]

Mammalian cells secrete calprotectin during the inflammatory response. Circulating activated platelets and platelet-leukocyte aggregates are increased in acute and chronic sterile thrombo-inflammatory diseases. Plasma calprotectin is elevated in persons with metabolic syndrome, a disease characterized by chronic inflammation.[21] Calprotectin is secreted in the mouth during inflammation of the gingiva and during oral candidiasis infection.[22][23] People who have mutations in the calprotectin gene appear susceptible to serious gum infections.[22] Manganese sequestration by calprotectin is likely important during lung inflammation.[8] The exact mechanism by which S100A8 and S100A9 is secreted by mammalian cells during inflammation remains unknown.[4] In lung autopsies from patients with inflammation caused by COVID-19, heterodimeric S100A8/A9 is mainly detected in neutrophils and deposited on vessel walls.[24] Platelet glycoprotein Ib alpha (GP1BA;GPIbα) is the receptor for S100A8/A9 on platelets.[24] In vitro, platelets adhere to and partially spread on S100A8/A9, leading to the formation of distinct populations of P-selectin+ and phosphatidylserine+ platelets. The prothrombotic pathway initiated by interaction of S100A8/A9 with GPIbα induces the formation of procoagulant platelets and fibrin (CD36 has a supporting role).[24]

Antimicrobial properties

Transition metals are essential to the survival of all organisms.[25] Mammals strictly limit metal availability as a part of the innate immune system, and this helps prevent infection by microbes and fungi.[25] Calprotectin was first described in the 1980s as a mammalian antimicrobial protein that acts through the sequestration of zinc.[1][2][10] It is now known that calprotectin also has antibacterial and antifungal properties that arise from its ability to sequester manganese and iron.[8][10][7] Calprotectin is the only known antimicrobial agent that acts through manganese sequestration.[10] Calprotectin is one of many antimicrobial effectors associated with neutrophil extracellular traps (NETs).[26]

Faecal calprotectin

Calprotectin becomes available in the intestinal lumen via leukocyte shedding,[1] active secretion,[2][12] cell disturbance, and cell death.[1][12] This results in elevated faecal calprotectin levels, which can be detected in the stool.[1][12] Elevated faecal calprotectin levels therefore indicate migration of neutrophils into the intestinal mucosa, which occurs during intestinal inflammation.[1][12][18] As people with active inflammatory bowel diseases (IBD) such as ulcerative colitis or Crohn's disease have as much as a 10-fold increase in faecal calprotectin levels,[11] the measurement of faecal calprotectin can serve as a biochemical test for these diseases.

Although a relatively new test, faecal calprotectin is regularly used as an indicator for IBD during treatment and as a diagnostic marker.[13] Faecal calprotectin tests can also function in distinguishing patients with irritable bowel syndrome from those with IBD.[1][12] Calprotectin is useful as a marker, as it is resistant to enzymatic degradation, and can be easily measured in faeces.[27] Although faecal calprotectin correlates significantly with disease activity in people with confirmed IBD,[28] elevated faecal calprotectin can be a false-positive indicator of IBD under some conditions. Importantly, intake of proton pump inhibitor is associated with significantly elevated calprotectin values.[29] Furthermore, positive faecal calprotectin does not help in localizing IBD, or in distinguishing ulcerative colitis from Crohn's disease.[1] Faecal calprotectin can also indicate other gastrointestinal conditions such as colorectal cancer, gastroenteritis, and food intolerance.[1] Calprotectin levels vary depending on age, comorbidity, and may vary day-to-day within individuals.[1] Faecal calprotectin could be used as a preliminary screen in otherwise functional patients suspected of having IBD, or as a means of following mucosal healing.[1] In patients with SARS-CoV-2 infection, elevated faecal calprotectin has been demonstrated to correlated with COVID-19 induced thrombosis even in patients without gastrointestinal symptoms.[30] The potential for using faecal calprotectin in this way is debated, however, and cut-off levels have not been agreed upon.[1]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 "The role and utility of faecal markers in inflammatory bowel disease". Therapeutic Advances in Gastroenterology 8 (1): 23–36. January 2015. doi:10.1177/1756283X14553384. PMID 25553077. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 "Calprotectin - a pleiotropic molecule in acute and chronic inflammation". Physiological Research 53 (3): 245–53. 2004. doi:10.33549/physiolres.930448. PMID 15209531. 
  3. ↑ Eisner, David; Neher, Erwin; Taschenberger, Holger; Smith, Godfrey (2023-10-01). "Physiology of intracellular calcium buffering" (in en). Physiological Reviews 103 (4): 2767–2845. doi:10.1152/physrev.00042.2022. ISSN 0031-9333. PMID 37326298. PMC 11550887. https://journals.physiology.org/doi/10.1152/physrev.00042.2022. 
  4. ↑ 4.0 4.1 4.2 4.3 Celio, Marco R.; Pauls, Thomas; Schwaller, Beat (1996). Guidebook to the calcium-binding proteins. Oxford: Sambrook & Tooze Publication at Oxford University Press. pp. 147–148. ISBN 0-19-859950-1. 
  5. ↑ 5.0 5.1 5.2 UniProt Consortium. "P05109- S10A8_HUMAN". UniProt Consortium. https://www.uniprot.org/uniprot/P05109. 
  6. ↑ 6.0 6.1 6.2 UniProt Consortium. "P06702- S10A9_HUMAN". UniProt Consortium. https://www.uniprot.org/uniprot/P06702. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 "Human calprotectin is an iron-sequestering host-defense protein". Nature Chemical Biology 11 (10): 765–71. October 2015. doi:10.1038/nchembio.1891. PMID 26302479. 
  8. ↑ 8.0 8.1 8.2 8.3 Costa, Lucio G; Aschner, Michael (2014). Manganese in Health and Disease. Royal Society of Chemistry. p. 146. ISBN 978-1-84973-943-6. https://books.google.com/books?id=3UG9BQAAQBAJ. Retrieved 27 January 2015. 
  9. ↑ Clark, HL (2016), "Zinc and manganese chelation by neutrophil s100a8/a9 (calprotectin) limits extracellular Aspergillus fumigatus hyphal growth and corneal infection", J Immunol 196 (1): 336–344, doi:10.4049/jimmunol.1502037, PMID 26582948. 
  10. ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 10.11 10.12 10.13 10.14 "Manganese and microbial pathogenesis: sequestration by the Mammalian immune system and utilization by microorganisms". ACS Chemical Biology 10 (3): 641–51. March 2015. doi:10.1021/cb500792b. PMID 25594606. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 Marshall, William Marshall; Lapsley, Marta; Day, Andrew; Ayling, Ruth (2014). Clinical Biochemistry: Metabolic and Clinical Aspects (3 ed.). Elsevier Health Sciences, 2014. ISBN 978-0-7020-5478-5. https://books.google.com/books?id=2FkXAwAAQBAJ&dq=faecal+calprotectin&pg=PT529. Retrieved 19 January 2015. 
  12. ↑ 12.00 12.01 12.02 12.03 12.04 12.05 12.06 12.07 12.08 12.09 Gupta, Ramesh (2014). Biomarkers in toxicology. San Diego, CA: Academic Press. pp. 272–273. ISBN 978-0-12-404649-8. https://books.google.com/books?id=EMpUAgAAQBAJ. Retrieved 19 January 2015. 
  13. ↑ 13.0 13.1 "Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis". BMJ 341. July 2010. doi:10.1136/bmj.c3369. PMID 20634346. 
  14. ↑ Pruenster, Monika; Vogl, Thomas; Roth, Johannes; Sperandio, Markus (November 2016). "S100A8/A9: From basic science to clinical application". Pharmacology & Therapeutics 167: 120–131. doi:10.1016/j.pharmthera.2016.07.015. ISSN 1879-016X. PMID 27492899. 
  15. ↑ Chan, James K.; Roth, Johannes; Oppenheim, Joost J.; Tracey, Kevin J.; Vogl, Thomas; Feldmann, Marc; Horwood, Nicole; Nanchahal, Jagdeep (August 2012). "Alarmins: awaiting a clinical response". The Journal of Clinical Investigation 122 (8): 2711–2719. doi:10.1172/JCI62423. ISSN 1558-8238. PMID 22850880. 
  16. ↑ UniProt Consortium. "P27005- S10A8_MOUSE". UniProt Consortium. https://www.uniprot.org/uniprot/P27005. 
  17. ↑ UniProt Consortium. "P31725- S10A9_MOUSE". UniProt Consortium. https://www.uniprot.org/uniprot/P31725. 
  18. ↑ 18.0 18.1 Evans, G.O. (2009). Animal Clinical Chemistry: A Practical Handbook for Toxicologists and Biomedical Researchers (2 ed.). Boca Raton: Taylor & Francis. pp. 107–108. ISBN 978-1-4200-8012-4. https://books.google.com/books?id=lIIDiaGfcrkC. Retrieved 19 January 2015. 
  19. ↑ "Calcium-induced noncovalently linked tetramers of MRP8 and MRP14 are confirmed by electrospray ionization-mass analysis". Journal of the American Society for Mass Spectrometry 11 (9): 780–8. September 2000. doi:10.1016/s1044-0305(00)00150-1. PMID 10976885. 
  20. ↑ 20.0 20.1 Maret, Wolfgang; Wedd, Anthony (2014). Binding, transport and storage of metal ions in biological cells. [S.l.]: Royal Soc Of Chemistry. p. 271. ISBN 978-1-84973-599-5. https://books.google.com/books?id=8ggdBAAAQBAJ. Retrieved 27 January 2015. 
  21. ↑ "Plasma calprotectin and its association with cardiovascular disease manifestations, obesity and the metabolic syndrome in type 2 diabetes mellitus patients". BMC Cardiovascular Disorders 14. December 2014. doi:10.1186/1471-2261-14-196. PMID 25527236. 
  22. ↑ 22.0 22.1 Schaechter, Moselio (2009). Encyclopedia of microbiology (3 ed.). [S.l.]: Elsevier. p. 570. ISBN 978-0-12-373944-5. https://books.google.com/books?id=rLhdW5YzuO4C. Retrieved 27 January 2015. 
  23. ↑ Vacharaksa, Anjalee (2007). Restricted HIV-1 Infection Increases Susceptibility of Candida Infection in Oral Keratinocytes. p. 20. ISBN 978-0-549-36766-6. https://books.google.com/books?id=Ces7swEMogwC. Retrieved 27 January 2015. 
  24. ↑ 24.0 24.1 24.2 "S100A8/A9 drives the formation of procoagulant platelets through GPIbα". Blood 2022 (24): 2626–2643. August 26, 2022. doi:10.1182/blood.2021014966. PMID 36026606. 
  25. ↑ 25.0 25.1 "Nutritional immunity: transition metals at the pathogen-host interface". Nature Reviews. Microbiology 10 (8): 525–37. July 2012. doi:10.1038/nrmicro2836. PMID 22796883. 
  26. ↑ Mahmoud, Asmaa H; Colombatti Olivieri, Maria A; Bannantine, John P; Abdellrazeq, Gaber S (2026-04-02). "Neutrophil biology and fate reprogramming in bacterial infections: mechanisms, plasticity, and therapeutic targeting" (in en). Journal of Leukocyte Biology 118 (4). doi:10.1093/jleuko/qiag033. ISSN 1938-3673. https://academic.oup.com/jleukbio/article/doi/10.1093/jleuko/qiag033/8544908. 
  27. ↑ "A simple method for assessing intestinal inflammation in Crohn's disease". Gut 47 (4): 506–13. October 2000. doi:10.1136/gut.47.4.506. PMID 10986210. 
  28. ↑ "Fecal calprotectin is a surrogate marker for endoscopic lesions in inflammatory bowel disease". Inflammatory Bowel Diseases 18 (12): 2218–24. December 2012. doi:10.1002/ibd.22917. PMID 22344983. 
  29. ↑ "Proton pump inhibitors are associated with elevation of faecal calprotectin and may affect specificity". European Journal of Gastroenterology & Hepatology 15 (5): 573–4; author reply 574. May 2003. doi:10.1097/00042737-200305000-00021. PMID 12702920. 
  30. ↑ Giuffrè, Mauro; Di Bella, Stefano; Sambataro, Gianluca; Zerbato, Verena; Cavallaro, Marco; Occhipinti, Alessandro Agostino; Palermo, Andrea; Crescenzi, Anna et al. (2020-09-16). "COVID-19-Induced Thrombosis in Patients without Gastrointestinal Symptoms and Elevated Fecal Calprotectin: Hypothesis Regarding Mechanism of Intestinal Damage Associated with COVID-19" (in en). Tropical Medicine and Infectious Disease 5 (3): 147. doi:10.3390/tropicalmed5030147. ISSN 2414-6366. PMID 32947803. 



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