The DOI matches its Crossref record; 47 of the 48 references it cites were found in a registry or an index.
Human calprotectin is an iron-sequestering host-defense protein
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“Site I binds Zn and Mn with high affinity as well as Fe and Ni, whereas site II binds Zn and Ni 86,87 .”
From Nutritional immunity: the battle for nutrient metals at the host–pathogen interface (2022) · cites this paper as [87]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Recent evidence, however, suggests that human calprotectin efficiently binds ferrous iron thereby reducing the availability of this nutrient to invading bacteria (Nakashige et al., 2015).”
From Iron in infection and immunity (2020) · cites this paper as Nakashige et al., 2015
The cited source says what the claim attributes to it.
In the citing paper
“Non-cofactor-associated Fe, in large part, is ligated by proteins, including transferrin, lactoferrin and calprotectin (4,9,10). Therefore, the ‘free’ or loosely ligated Fe concentrations within host tissues are low to restrict pathogen growth (11).”
From The Staphylococcus aureus non-coding RNA IsrR regulates TCA cycle activity and virulence (2025) · cites this paper as [10]
In the citing paper
“though recent reports revealed that calprotectin also binds ferrous iron, nickel, and copper in vitro (Besold et al., 2017; Nakashige et al., 2015; Nakashige et al., 2017).”
From The Impact of Dietary Transition Metals on Host-Bacterial Interactions (2018) · cites this paper as Nakashige et al., 2015
In the citing paper
“Calprotectin primarily binds zinc and manganese during infection”
From The Impact of Dietary Transition Metals on Host-Bacterial Interactions (2018) · cites this paper as Nakashige et al., 2015
In the citing paper
“In addition, neutrophils produce large amounts of calprotectin and lactoferrin, both of which scavenge iron, thereby inhibiting bacterial proliferation (Nakashige et al., 2015).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Nakashige et al., 2015
In the citing paper
“CP is not only able to sequester Mn 2+ and Zn 2+ , but also Fe 2+ [94] thereby limiting those metals availability for invading microbes”
From Iron in immune cell function and host defense (2021) · cites this paper as [94]
In the citing paper
“Recent work showed that Fe2+ binding by calprotectin contributes to inhibition of bacterial growth in vitro, an activity that remains to be investigated during infection (98).”
From Transition Metals and Virulence in Bacteria (2016) · cites this paper as [98]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Ferrozine---a new spectrophotometric reagent for iron
Stookey, L. L. (1970) · Analytical Chemistry · doi:10.1021/ac60289a016 · Cited by 4,712
Greenwood, N. N., & Gibb, T. C. (1966) · Elsevier eBooks · doi:10.1007/978-94-009-5697-1 · Cited by 2,886
637. The stability of transition-metal complexes
Irving, H., & Williams, R. J. P. (1953) · Journal of the Chemical Society (Resumed) · doi:10.1039/jr9530003192 · Cited by 2,116
Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron
Flo, T. H., Smith, K. D., Sato, S., Rodriguez, D. J., Holmes, M. A., Strong, R. K., Akira, S., & Aderem, A. (2004) · Nature · doi:10.1038/nature03104 · Cited by 1,877
Nutritional immunity: transition metals at the pathogen–host interface
Hood, M. I., & Skaar, E. P. (2012) · Nature Reviews Microbiology · doi:10.1038/nrmicro2836 · Cited by 1,535
Iron in infection and immunity
Cassat, J. E., & Skaar, E. P. (2013) · Cell Host & Microbe · doi:10.1016/j.chom.2013.04.010 · Cited by 1,214
A component of innate immunity prevents bacterial biofilm development
Singh, P. K., Parsek, M. R., Greenberg, E. P., & Welsh, M. J. (2002) · Nature · doi:10.1038/417552a · Cited by 1,026
Metal Chelation and Inhibition of Bacterial Growth in Tissue Abscesses
Corbin, B. D., Seeley, E. H., Raab, A., Feldmann, J., Miller, M. R., Torres, V. J., Anderson, K. L., Dattilo, B. M., Dunman, P. M., Gerads, R., et al. (2008) · Science · doi:10.1126/science.1152449 · Cited by 857
Carter, P. M. (1971) · Analytical Biochemistry · doi:10.1016/0003-2697(71)90405-2 · Cited by 787
A New Cell-Permeable Fluorescent Probe for Zn2+
Walkup, G. K., Burdette, S. C., Lippard, S. J., & Tsien, R. Y. (2000) · Journal of the American Chemical Society · doi:10.1021/ja000868p · Cited by 572
Kehl-Fie, T. E., Chitayat, S., Hood, M. I., Damo, S., Restrepo, N., Garcia, C., Munro, K. A., Chazin, W. J., & Skaar, E. P. (2011) · Cell Host & Microbe · doi:10.1016/j.chom.2011.07.004 · Cited by 419
Damo, S. M., Kehl-Fie, T. E., Sugitani, N., Holt, M. E., Rathi, S., Murphy, W. J., Zhang, Y., Betz, C., Hench, L., Fritz, G., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1220341110 · Cited by 388
Manganese and Defenses against Oxygen Toxicity in Lactobacillus plantarum
Archibald, F. S., & Fridovich, I. (1981) · Journal of Bacteriology · doi:10.1128/jb.145.1.442-451.1981 · Cited by 373
Feo – Transport of Ferrous Iron into Bacteria
Cartron, M. L., Maddocks, S., Gillingham, P., Craven, C. J., & Andrews, S. C. (2006) · BioMetals · doi:10.1007/s10534-006-0003-2 · Cited by 366
Nutritional Immunity: Host's Attempt to Withhold Iron From Microbial Invaders
Weinberg, E. D. (1975) · JAMA · doi:10.1001/jama.1975.03240130021018 · Cited by 342
Liu, J. Z., Jellbauer, S., Poe, A. J., Ton, V., Pesciaroli, M., Kehl-Fie, T. E., Restrepo, N. A., Hosking, M. P., Edwards, R. A., Battistoni, A., et al. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.01.017 · Cited by 328
How pathogenic bacteria evade mammalian sabotage in the battle for iron
Fischbach, M. A., Lin, H., Liu, D. R., & Walsh, C. T. (2006) · Nature Chemical Biology · doi:10.1038/nchembio771 · Cited by 321
Frey, P. A., & Reed, G. H. (2012) · ACS Chemical Biology · doi:10.1021/cb300323q · Cited by 299
Velayudhan, J., Hughes, N. J., McColm, A. A., Bagshaw, J. A., Clayton, C. L., Andrews, S. C., & Kelly, D. J. (2000) · Molecular Microbiology · doi:10.1046/j.1365-2958.2000.01987.x · Cited by 298
Characterization and application of FerroZine iron reagent as a ferrous iron indicator
Gibbs, C. R. (1976) · Analytical Chemistry · doi:10.1021/ac50002a034 · Cited by 291
Korndörfer, I. P., Brueckner, F., & Skerra, A. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.04.065 · Cited by 284
Manganese Transport and the Role of Manganese in Virulence
Papp‐Wallace, K. M., & Maguire, M. E. (2006) · Annual Review of Microbiology · doi:10.1146/annurev.micro.60.080805.142149 · Cited by 280
Biophysical characterization of S100A8 and S100A9 in the absence and presence of bivalent cations
Vogl, T., Leukert, N., Barczyk, K., Strupat, K., & Roth, J. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.08.028 · Cited by 176
Complexation of iron(III) and iron(II) by citrate. Implications for iron speciation in blood plasma
Königsberger, L.-C., Königsberger, E., May, P. M., & Hefter, G. T. (2000) · Journal of Inorganic Biochemistry · doi:10.1016/s0162-0134(99)00222-6 · Cited by 168
Calcium Ion Gradients Modulate the Zinc Affinity and Antibacterial Activity of Human Calprotectin
Brophy, M. B., Hayden, J. A., & Nolan, E. M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja307974e · Cited by 158
Self-citationCotruvo, J. A., & Stubbe, J. (2012) · Metallomics · doi:10.1039/c2mt20142a · Cited by 146
Brodersen, D. E., Nyborg, J., & Kjeldgaard, M. (1999) · Biochemistry · doi:10.1021/bi982483d · Cited by 139
The Zinc-Reversible Antimicrobial Activity of Neutrophil Lysates and Abscess Fluid Supernatants
Sohnle, P. G., Collins-Lech, C., & Wiessner, J. H. (1991) · The Journal of Infectious Diseases · doi:10.1093/infdis/164.1.137 · Cited by 135
Mills, S. A., & Marletta, M. A. (2005) · Biochemistry · doi:10.1021/bi0507579 · Cited by 131
Hayden, J. A., Brophy, M. B., Cunden, L. S., & Nolan, E. M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja3096416 · Cited by 131
Self-citationTransition metal ions at the crossroads of mucosal immunity and microbial pathogenesis
Diaz-Ochoa, V. E., Jellbauer, S., Klaus, S., & Raffatellu, M. (2014) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2014.00002 · Cited by 129
Manganese acquisition and homeostasis at the host-pathogen interface
Lisher, J. P., & Giedroc, D. P. (2013) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2013.00091 · Cited by 127
Konings, A. F., Martin, L. W., SHARPLES, K. J., Roddam, L. F., Latham, R. D., Reid, D. W., & Lamont, I. L. (2013) · Infection and Immunity · doi:10.1128/iai.00418-13 · Cited by 121
Interplay between manganese and zinc homeostasis in the human pathogen Streptococcus pneumoniae
Jacobsen, F. E., Kazmierczak, K. M., Lisher, J. P., Winkler, M. E., & Giedroc, D. P. (2010) · Metallomics · doi:10.1039/c0mt00050g · Cited by 118
Stojiljković, I., Cobeljić, M., & Hantke, K. (1993) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.1993.tb06082.x · Cited by 111
Moroz, O. V., Blagova, E. V., Wilkinson, A. J., Wilson, K. S., & Bronstein, I. B. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.06.004 · Cited by 99
Brophy, M. B., & Nolan, E. M. (2015) · ACS Chemical Biology · doi:10.1021/cb500792b · Cited by 89
Self-citationAguirre, J. D., Clark, H. M., McIlvin, M., Vazquez, C., Palmere, S. L., Grab, D. J., Seshu, J., Hart, P. J., Saito, M., & Culotta, V. C. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.433540 · Cited by 82
Brophy, M. B., Nakashige, T. G., Gaillard, A., & Nolan, E. M. (2013) · Journal of the American Chemical Society · doi:10.1021/ja407147d · Cited by 74
Self-citationGagnon, D. M., Brophy, M. B., Bowman, S. E. J., Stich, T. A., Drennan, C. L., Britt, R. D., & Nolan, E. M. (2015) · Journal of the American Chemical Society · doi:10.1021/ja512204s · Cited by 74
Self-citationBossek, U., Nühlen, D., Bill, E., Glaser, T., Krebs, C., Weyhermüller, T., Wieghardt, K. E., Lengen, M., & TRAUTWEIN, A. X. (1997) · Inorganic Chemistry · doi:10.1021/ic970119h · Cited by 60
Self-citationMizuno, K., Whittaker, M. M., Bächinger, H. P., & Whittaker, J. W. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400813200 · Cited by 58
Ostendorp, T., Diez, J., Heizmann, C. W., & Fritz, G. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2010.10.006 · Cited by 49
Mn 2+ and bacterial pathogenesis
Michelle, L. Z. (2004) · Frontiers in bioscience · doi:10.2741/1317 · Cited by 45
Spectroscopic and Structural Characterization of the [Fe(imidazole)6]2+ Cation
Carver, G., Tregenna‐Piggott, P. L. W., Barra, A., Neels, A., & Stride, J. A. (2003) · Inorganic Chemistry · doi:10.1021/ic034110t · Cited by 42
Motional effects in the mössbauer spectra of iron(II) hexammines
Asch, L., Adloff, J. P., Friedt, J. M., & Danon, J. (1970) · Chemical Physics Letters · doi:10.1016/0009-2614(70)80014-8 · Cited by 22
Hexakis(1H-imidazole-κN3)iron(II) sulfate–1H-imidazole (1/2)
Nistor, A., Shova, S. G., Cazacu, M., & Lazar, A. (2011) · Acta Crystallographica Section E Structure Reports Online · doi:10.1107/s1600536811043169 · Cited by 2
Cited by
Sorted by citations
Nutritional immunity: the battle for nutrient metals at the host–pathogen interface
Murdoch, C. C., & Skaar, E. P. (2022) · Nature Reviews Microbiology · doi:10.1038/s41579-022-00745-6 · Cited by 701
Transition Metals and Virulence in Bacteria
Palmer, L. D., & Skaar, E. P. (2016) · Annual Review of Genetics · doi:10.1146/annurev-genet-120215-035146 · Cited by 449
Antimicrobial peptides and wound healing: biological and therapeutic considerations
Mangoni, M. L., McDermott, A. M., & ZASLOFF, M. A. (2016) · Experimental Dermatology · doi:10.1111/exd.12929 · Cited by 427
Iron in infection and immunity
Nairz, M., & Weiss, G. (2020) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2020.100864 · Cited by 359
A Pseudomonas T6SS effector recruits PQS-containing outer membrane vesicles for iron acquisition
Lin, J., Zhang, W., Cheng, J., Xu, Y., Zhu, K., Wang, Y., Wei, G., Qian, P., Luo, Z., & Shen, X. (2017) · Nature Communications · doi:10.1038/ncomms14888 · Cited by 330
Metadata
- Authors
- Nakashige, T. G., Zhang, B., Krebs, C., & Nolan, E. M.
- Affiliations
- Massachusetts Institute of Technology (US)
- Pennsylvania State University (US)
- Corresponding author
- Nolan, Elizabeth M
- Venue
- Nature Chemical Biology
- Published
- 2015-08-24
- Volume
- 11
- Issue
- 10
- Pages
- 765-771
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC4575267
- OpenAlex
- W1143127356
- Semantic Scholar
- 393a038c3a86f6e450d91c504b22118bd86ec29c
- Cited by
- 291
- References
- 48
- Citations by year
- 2026: 17 · 2025: 26 · 2024: 23 · 2023: 33 · 2022: 30 · 2021: 35 · 2020: 33 · 2019: 24 · 2018: 21 · 2017: 27 · 2016: 18 · 2015: 4
- FWCI
- 9.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- PMC
- Funders
- National Institutes of Health (1dp2od007045-01)
- National Institute of Allergy and Infectious Diseases (HHSN272200700055C)
- National Institute of Environmental Health Sciences (P30ES002109)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- calprotectin, iron chelation, antimicrobial host defense, innate immunity, iron coordination chemistry, high-spin Fe(II), Mössbauer spectroscopy
- MeSH terms
- Calcium, Electron Spin Resonance Spectroscopy, Escherichia coli, Humans, Iron, Iron Chelating Agents, Microbial Sensitivity Tests, Staphylococcus aureus, Spectroscopy, Mossbauer, Leukocyte L1 Antigen Complex, Lactiplantibacillus plantarum, Host-Pathogen Interactions
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
