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词条 Calprotectin
释义

  1. Structure

      Metal binding  

  2. Inflammatory disease

  3. Antimicrobial properties

  4. Faecal calprotectin

  5. See also

  6. References

Calprotectin is a complex of the mammalian proteins S100A8 and S100A9.[1][2] In the presence of calcium, calprotectin is capable of sequestering the transition metals iron,[1] manganese and zinc[2][5] via chelation.[2] This metal sequestration affords the complex antimicrobial properties.[2][5] Calprotectin is the only known antimicrobial manganese sequestration protein complex.[9] 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.[13] Faecal calprotectin has been used to detect intestinal inflammation (colitis or enteritis) and can serve as a biomarker for inflammatory bowel diseases and Rheumatoid Arthritis. [11][15] Other names for calprotectin include MRP8-MRP14, calgranulin A and B, cystic fibrosis antigen, L1, 60BB antigen, and 27E10 antigen.[2][13]

Structure

The human homologue of calprotectin is a 24 kDa dimer,[9] and is formed by the protein monomers S100A8 (10,835 Da) and S100A9 (13,242 Da).[19][20] The primary structure of calprotectin can vary between species. For instance, the mouse homologue of S100A8 is 10,295 Da,[21] while the S100A9 homologue is 13,049 Da.[22] 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][27][1] Each of S100A8 and S100A9 contain two EF-hand type Ca2+ binding sites,[9][13] and calprotectin is able to bind a total of four calcium ions per dimer or eight calcium ions per tetramer.[31] Calcium binding induces a conformational change in the complex that improves its affinity for transition metals, and promotes tetramer formation.[2][9] A maximum of two transition metal ions may bind to each calprotectin S100A8-S100A9 dimer.[9]

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.[9][36][1] 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.[9] 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][19][20]

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).[9] 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.[9] 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.[9] Manganese or iron are bound by the calprotectin dimer at this His6 site.[9][1] Zinc can be bound to either of the sites that form at the interface between S100A8 and S100A9 monomers.[9][36]

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. Plasma calprotectin is elevated in persons with metabolic syndrome, a disease characterized by chronic inflammation.[3] Calprotectin is secreted in the mouth during inflammation of the gingiva and during oral candidiasis infection.[58][59] People who have mutations in the calprotectin gene appear susceptible to serious gum infections.[58] Manganese sequestration by calprotectin is likely important during lung inflammation.[5] The exact mechanism by which S100A8 and S100A9 is secreted by mammalian cells during inflammation remains unknown.[13]

Antimicrobial properties

Transition metals are essential to the survival of all organisms. Mammals strictly limit metal availability as a part of the innate immune system, and this helps prevent infection by microbes and fungi. Calprotectin was first described in the 1980s as a mammalian antimicrobial protein that acts through the sequestration of zinc.[1][2][9] It is now known that calprotectin also has antibacterial and antifungal properties that arise from its ability to sequester manganese and iron.[5][9][1] Calprotectin is the only known antimicrobial agent that acts through manganese sequestration.[9]

Faecal calprotectin

{{see also|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][27] As people with active inflammatory bowel diseases (IBD) such as ulcerative colitis or Crohn 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.[15] 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.[86] Although faecal calprotectin correlates significantly with disease activity in people with confirmed IBD,[87] 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.[88] 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] The potential for using faecal calprotectin in this way is debated, however, and cut-off levels have not been agreed upon.[1]

See also

  • Zinc in biology
  • Manganese in biology
  • Nutritional role of calcium
  • Bioinorganic Chemistry

References

1. ^1 2 3 4 {{cite journal | vauthors = Nakashige TG, Zhang B, Krebs C, Nolan EM | title = Human calprotectin is an iron-sequestering host-defense protein | journal = Nature Chemical Biology | volume = 11 | issue = 10 | pages = 765–71 | date = October 2015 | pmid = 26302479 | pmc = 4575267 | doi = 10.1038/nchembio.1891 }}
2. ^{{Citation |last=Clark |first=HL |display-authors=etal |year=2016 |title=Zinc and manganese chelation by neutrophil s100a8/a9 (calprotectin) limits extracellular Aspergillus fumigatus hyphal growth and corneal infection |journal=J Immunol |volume=196 |issue=1 |pages=336–344 |pmid=26582948 |pmc= 4684987|doi=10.4049/jimmunol.1502037 |postscript=.}}
3. ^{{cite journal | vauthors = Pedersen L, Nybo M, Poulsen MK, Henriksen JE, Dahl J, Rasmussen LM | title = Plasma calprotectin and its association with cardiovascular disease manifestations, obesity and the metabolic syndrome in type 2 diabetes mellitus patients | journal = BMC Cardiovascular Disorders | volume = 14 | pages = 196 | date = December 2014 | pmid = 25527236 | doi = 10.1186/1471-2261-14-196 | url = https://bmccardiovascdisord.biomedcentral.com/articles/10.1186/1471-2261-14-196 | PMC = 4289556 }}
4. ^1 2 {{cite book|last1=Maret|first1=Wolfgang|last2=Wedd|first2=Anthony|title=Binding, transport and storage of metal ions in biological cells|date=2014|publisher=Royal Soc Of Chemistry|location=[S.l.]|isbn=9781849735995|page=271|url=https://books.google.com/?id=8ggdBAAAQBAJ&printsec=frontcover|access-date=27 January 2015}}
5. ^1 {{cite book|last1=Vacharaksa|first1=Anjalee|title=Restricted HIV-1 Infection Increases Susceptibility of Candida Infection in Oral Keratinocytes|date=2007|publisher=ProQuest|isbn=9780549367666|page=20|url=https://books.google.com/?id=Ces7swEMogwC&printsec=frontcover|access-date=27 January 2015}}
6. ^1 2 {{cite book|last1=Schaechter|first1=Moselio|title=Encyclopedia of microbiology|date=2009|publisher=Elsevier|location=[S.l.]|isbn=0123739446|page=570|edition=3|url=https://books.google.ca/books?id=rLhdW5YzuO4C&printsec=frontcover|access-date=27 January 2015}}
7. ^1 2 3 4 {{cite book|last1=Costa|first1=Lucio G|last2=Aschner|first2=Michael|title=Manganese in Health and Disease|date=2014|publisher=Royal Society of Chemistry|isbn=1849739439|page=146|url=https://books.google.ca/books?id=3UG9BQAAQBAJ&printsec=frontcover|access-date=27 January 2015}}
8. ^1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 {{cite journal | vauthors = Brophy MB, Nolan EM | title = Manganese and microbial pathogenesis: sequestration by the Mammalian immune system and utilization by microorganisms | journal = ACS Chemical Biology | volume = 10 | issue = 3 | pages = 641–51 | date = March 2015 | pmid = 25594606 | doi = 10.1021/cb500792b }}
9. ^1 2 3 4 {{cite book|last1=Celio|first1=Marco R.|last2=Pauls|first2=Thomas|last3=Schwaller|first3=Beat|title=Guidebook to the calcium-binding proteins|date=1996|publisher=Sambrook & Tooze Publication at Oxford University Press|location=Oxford|isbn=0198599501|pages=147–148}}
10. ^1 {{cite web |last1= UniProt Consortium |title= P31725- S10A9_MOUSE |url= https://www.uniprot.org/uniprot/P31725 |website= www.uniprot.org |publisher=UniProt Consortium |access-date= 21 January 2015}}
11. ^1 {{cite web |last1= UniProt Consortium |title= P27005- S10A8_MOUSE |url= https://www.uniprot.org/uniprot/P27005 |website= www.uniprot.org |publisher= UniProt Consortium |access-date= 21 January 2015}}
12. ^1 2 {{cite web |last1= UniProt Consortium |title= P05109- S10A8_HUMAN |url= https://www.uniprot.org/uniprot/P05109 |website= www.uniprot.org |publisher= UniProt Consortium |access-date= 21 January 2015}}
13. ^1 2 {{cite web |last1= UniProt Consortium |title= P06702- S10A9_HUMAN |url= https://www.uniprot.org/uniprot/P06702 |website= www.uniprot.org |publisher=UniProt Consortium |access-date= 21 January 2015}}
14. ^1 {{cite journal | vauthors = Strupat K, Rogniaux H, Van Dorsselaer A, Roth J, Vogl T | title = Calcium-induced noncovalently linked tetramers of MRP8 and MRP14 are confirmed by electrospray ionization-mass analysis | journal = Journal of the American Society for Mass Spectrometry | volume = 11 | issue = 9 | pages = 780–8 | date = September 2000 | pmid = 10976885 | doi = 10.1016/s1044-0305(00)00150-1 }}
15. ^1 2 3 4 5 6 7 8 9 10 11 12 13 14 {{cite journal | vauthors = Stríz I, Trebichavský I | title = Calprotectin - a pleiotropic molecule in acute and chronic inflammation | journal = Physiological Research | volume = 53 | issue = 3 | pages = 245–53 | date = 2004 | pmid = 15209531 }}
16. ^1 2 3 4 5 6 7 8 9 10 11 12 {{cite journal | vauthors = Lehmann FS, Burri E, Beglinger C | title = The role and utility of faecal markers in inflammatory bowel disease | journal = Therapeutic Advances in Gastroenterology | volume = 8 | issue = 1 | pages = 23–36 | date = January 2015 | pmid = 25553077 | pmc = 4265086 | doi = 10.1177/1756283X14553384 }}
17. ^1 2 {{cite book|last1=Evans|first1=G.O.|title=Animal Clinical Chemistry: A Practical Handbook for Toxicologists and Biomedical Researchers|date=2009|publisher=Taylor & Francis|location=Boca Raton|isbn=9781420080124|pages=107–108|edition=2|url=https://books.google.com/?id=lIIDiaGfcrkC&printsec=frontcover#v=onepage&q&f=false|access-date=19 January 2015}}
18. ^1 2 3 4 5 6 7 8 9 10 {{cite book|last1=Gupta|first1=Ramesh|title=Biomarkers in toxicology|date=2014|publisher=Academic Press|location=San Diego, CA|isbn=9780124046498|pages=272–273|url=https://books.google.com/?id=EMpUAgAAQBAJ&printsec=frontcover#v=onepage&q&f=false|access-date=19 January 2015}}
19. ^1 2 3 4 5 6 {{cite book|last1=Marshall|first1=William Marshall,|last2=Lapsley|first2=Marta|last3=Day|first3=Andrew|last4=Ayling|first4=Ruth|title=Clinical Biochemistry: Metabolic and Clinical Aspects|date=2014|publisher=Elsevier Health Sciences, 2014|isbn=9780702054785|edition=3|url=https://books.google.com/?id=2FkXAwAAQBAJ&pg=PT529&dq=faecal+calprotectin#v=onepage&q=faecal%20calprotectin&f=false|access-date=19 January 2015}}
20. ^1 2 {{cite journal | vauthors = van Rheenen PF, Van de Vijver E, Fidler V | title = Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis | journal = BMJ | volume = 341 | issue = | pages = c3369 | date = July 2010 | pmid = 20634346 | pmc = 2904879 | doi = 10.1136/bmj.c3369 | laysummary = http://www.medscape.com/viewarticle/725672 | laysource = MedScape }}
21. ^1 {{cite journal | vauthors = Tibble J, Teahon K, Thjodleifsson B, Roseth A, Sigthorsson G, Bridger S, Foster R, Sherwood R, Fagerhol M, Bjarnason I | title = A simple method for assessing intestinal inflammation in Crohn's disease | journal = Gut | volume = 47 | issue = 4 | pages = 506–13 | date = October 2000 | pmid = 10986210 | pmc = 1728060 | doi = 10.1136/gut.47.4.506 }}
22. ^1 {{cite journal | vauthors = D'Haens G, Ferrante M, Vermeire S, Baert F, Noman M, Moortgat L, Geens P, Iwens D, Aerden I, Van Assche G, Van Olmen G, Rutgeerts P | title = Fecal calprotectin is a surrogate marker for endoscopic lesions in inflammatory bowel disease | journal = Inflammatory Bowel Diseases | volume = 18 | issue = 12 | pages = 2218–24 | date = December 2012 | pmid = 22344983 | doi = 10.1002/ibd.22917 }}
23. ^1 {{cite journal | vauthors = Poullis A, Foster R, Mendall MA, Shreeve D, Wiener K | title = Proton pump inhibitors are associated with elevation of faecal calprotectin and may affect specificity | journal = European Journal of Gastroenterology & Hepatology | volume = 15 | issue = 5 | pages = 573–4; author reply 574 | date = May 2003 | pmid = 12702920 | doi = 10.1097/00042737-200305000-00021 }}
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2 : Protein complexes|S100 proteins
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