Calprotectin

Calprotectin is a complex of the mammalian proteins S100A8 and S100A9.[1][2]Other names for calprotectin include MRP8-MRP14, calgranulin A and B, cystic fibrosis antigen, L1, 60BB antigen, and 27E10 antigen.[2][3] In the presence of calcium, calprotectin is capable of sequestering the transition metals iron,[4]manganese and zinc[2][5] via chelation.[6] This metal sequestration affords the complex antimicrobial properties.[2][5] Calprotectin is the only known antimicrobial manganese sequestration protein complex.[7] Calprotectin comprises as much as 60% of the soluble protein content of the cytosol of a neutrophil,[2][8][9] and it is secreted by an unknown mechanism during inflammation.[3]Faecal calprotectin has been used to detect intestinal inflammation (colitis or enteritis) and can serve as a biomarker for inflammatory bowel diseases.[8][10] 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.[11][12]

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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 kDadimer,[7] and is formed by the protein monomers S100A8 (10,835 Da) and S100A9 (13,242 Da).[13][14] The primary structure of calprotectin can vary between species. For instance, the mouse homologue of S100A8 is 10,295 Da,[15] while the S100A9 homologue is 13,049 Da.[16] Early size exclusion chromatography experiments incorrectly indicated that calprotectin had a molecular mass of 36.5 kDa;[2][9] occasionally this value is used in contemporary literature. Calprotectin S100A8-S100A9 dimers can non-covalently pair with one another to form 48 kDa tetramers.

Calprotectin has a high affinity for calcium, zinc, iron, and manganese.[8][9][17][4] Each of S100A8 and S100A9 contain two EF-hand type Ca2+ binding sites,[7][3] and calprotectin is able to bind a total of four calcium ions per dimer or eight calcium ions per tetramer.[18] Calcium binding induces a conformational change in the complex that improves its affinity for transition metals, and promotes tetramer formation.[2][7] A maximum of two transition metal ions may bind to each calprotectin S100A8-S100A9 dimer.[7]

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.[7][19][4] 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.[7] 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][13][14]

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).[7] 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.[7] 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.[7] Manganese or iron are bound by the calprotectin dimer at this His6 site.[7][4] Zinc can be bound to either of the sites that form at the interface between S100A8 and S100A9 monomers.[7][19]

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