Human Calprotectin is an Iron-sequestering Host-defense Protein

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2015 Aug 25

PMID 26302479

Citations 163

Authors

Toshiki G Nakashige

Bo Zhang

Carsten Krebs

Elizabeth M Nolan

Affiliations

Soon will be listed here.

Abstract

Human calprotectin (CP) is a metal-chelating antimicrobial protein of the innate immune response. The current working model states that CP sequesters manganese and zinc from pathogens. We report the discovery that CP chelates iron and deprives bacteria of this essential nutrient. Elemental analysis of CP-treated growth medium establishes that CP reduces the concentrations of manganese, iron and zinc. Microbial growth studies reveal that iron depletion by CP contributes to the growth inhibition of bacterial pathogens. Biochemical investigations demonstrate that CP coordinates Fe(II) at an unusual hexahistidine motif, and the Mössbauer spectrum of (57)Fe(II)-bound CP is consistent with coordination of high-spin Fe(II) at this site (δ = 1.20 mm/s, ΔEQ = 1.78 mm/s). In the presence of Ca(II), CP turns on its iron-sequestering function and exhibits subpicomolar affinity for Fe(II). Our findings expand the biological coordination chemistry of iron and support a previously unappreciated role for CP in mammalian iron homeostasis.

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References

Cartron M, Maddocks S, Gillingham P, Craven C, Andrews S . Feo--transport of ferrous iron into bacteria. Biometals. 2006; 19(2):143-57. DOI: 10.1007/s10534-006-0003-2. View

Korndorfer I, Brueckner F, Skerra A . The crystal structure of the human (S100A8/S100A9)2 heterotetramer, calprotectin, illustrates how conformational changes of interacting alpha-helices can determine specific association of two EF-hand proteins. J Mol Biol. 2007; 370(5):887-98. DOI: 10.1016/j.jmb.2007.04.065. View

Gagnon D, Brophy M, Bowman S, Stich T, Drennan C, Britt R . 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; 137(8):3004-16. PMC: 4354957. DOI: 10.1021/ja512204s. View

Singh P, Parsek M, Greenberg E, Welsh M . A component of innate immunity prevents bacterial biofilm development. Nature. 2002; 417(6888):552-5. DOI: 10.1038/417552a. View

Papp-Wallace K, Maguire M . Manganese transport and the role of manganese in virulence. Annu Rev Microbiol. 2006; 60:187-209. DOI: 10.1146/annurev.micro.60.080805.142149. View

Archibald F, Fridovich I . Manganese and defenses against oxygen toxicity in Lactobacillus plantarum. J Bacteriol. 1981; 145(1):442-51. PMC: 217292. DOI: 10.1128/jb.145.1.442-451.1981. View

Jacobsen F, Kazmierczak K, Lisher J, Winkler M, Giedroc D . Interplay between manganese and zinc homeostasis in the human pathogen Streptococcus pneumoniae. Metallomics. 2011; 3(1):38-41. PMC: 3061551. DOI: 10.1039/c0mt00050g. View

Mizuno K, Whittaker M, Bachinger H, Whittaker J . Calorimetric studies on the tight binding metal interactions of Escherichia coli manganese superoxide dismutase. J Biol Chem. 2004; 279(26):27339-44. DOI: 10.1074/jbc.M400813200. View

Hayden J, Brophy M, Cunden L, Nolan E . High-affinity manganese coordination by human calprotectin is calcium-dependent and requires the histidine-rich site formed at the dimer interface. J Am Chem Soc. 2013; 135(2):775-87. PMC: 3575579. DOI: 10.1021/ja3096416. View

10.

Zaharik M, Finlay B . Mn2+ and bacterial pathogenesis. Front Biosci. 2004; 9:1035-42. DOI: 10.2741/1317. View

11.

Moroz O, Blagova E, Wilkinson A, Wilson K, Bronstein I . The crystal structures of human S100A12 in apo form and in complex with zinc: new insights into S100A12 oligomerisation. J Mol Biol. 2009; 391(3):536-51. DOI: 10.1016/j.jmb.2009.06.004. View

12.

Liu J, Jellbauer S, Poe A, Ton V, Pesciaroli M, Kehl-Fie T . Zinc sequestration by the neutrophil protein calprotectin enhances Salmonella growth in the inflamed gut. Cell Host Microbe. 2012; 11(3):227-39. PMC: 3308348. DOI: 10.1016/j.chom.2012.01.017. View

13.

Kehl-Fie T, Chitayat S, Hood M, Damo S, Restrepo N, Garcia C . Nutrient metal sequestration by calprotectin inhibits bacterial superoxide defense, enhancing neutrophil killing of Staphylococcus aureus. Cell Host Microbe. 2011; 10(2):158-64. PMC: 3157011. DOI: 10.1016/j.chom.2011.07.004. View

14.

Frey P, Reed G . The ubiquity of iron. ACS Chem Biol. 2012; 7(9):1477-81. DOI: 10.1021/cb300323q. View

15.

Brophy M, Nolan E . Manganese and microbial pathogenesis: sequestration by the Mammalian immune system and utilization by microorganisms. ACS Chem Biol. 2015; 10(3):641-51. PMC: 4372095. DOI: 10.1021/cb500792b. View

16.

Carver G, Tregenna-Piggott P, Barra A, Neels A, Stride J . Spectroscopic and structural characterization of the [Fe(imidazole)(6)](2+) cation. Inorg Chem. 2003; 42(18):5771-7. DOI: 10.1021/ic034110t. View

17.

Hood M, Skaar E . Nutritional immunity: transition metals at the pathogen-host interface. Nat Rev Microbiol. 2012; 10(8):525-37. PMC: 3875331. DOI: 10.1038/nrmicro2836. View

18.

Lisher J, Giedroc D . Manganese acquisition and homeostasis at the host-pathogen interface. Front Cell Infect Microbiol. 2013; 3:91. PMC: 3851752. DOI: 10.3389/fcimb.2013.00091. View

19.

Damo S, Kehl-Fie T, Sugitani N, Holt M, Rathi S, Murphy W . Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens. Proc Natl Acad Sci U S A. 2013; 110(10):3841-6. PMC: 3593839. DOI: 10.1073/pnas.1220341110. View

20.

Weinberg E . Nutritional immunity. Host's attempt to withold iron from microbial invaders. JAMA. 1975; 231(1):39-41. DOI: 10.1001/jama.231.1.39. View