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.
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Site I binds Zn and Mn with high affinity as well as Fe and Ni, whereas site II binds Zn and Ni.
“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]
The Introduction (page unavailable) says site 1 binds Zn(II) with high affinity but has relatively weak affinity for Mn(II); it assigns high-affinity Mn(II) binding to site 2 instead. The Results section on metal selectivity (page unavailable) also describes Fe(II) binding at site 2, not site 1. The passages do not establish the claimed site-specific Ni(II) binding. (LLM, conf=0.89)
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Experimental — accuracy not yet measuredHuman calprotectin efficiently binds ferrous iron, thereby reducing the availability of this nutrient to invading bacteria.
“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
Inside the host, non-cofactor-associated Fe is largely ligated by proteins including transferrin, lactoferrin and calprotectin, so free or loosely ligated Fe concentrations within host tissues are low to restrict pathogen growth.
“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 <i>Staphylococcus aureus</i> non-coding RNA IsrR regulates TCA cycle activity and virulence (2025) · cites this paper as [10]
Calprotectin also binds ferrous iron, nickel, and copper in vitro.
“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
Calprotectin primarily binds zinc and manganese during infection.
“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
Neutrophils produce large amounts of calprotectin and lactoferrin, both of which scavenge iron, thereby inhibiting bacterial proliferation.
“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
Calprotectin is able to sequester Mn2+ and Zn2+, but also Fe2+, thereby limiting those metals' availability for invading microbes.
“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]
Fe2+ binding by calprotectin contributes to inhibition of bacterial growth in vitro.
“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]
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- 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
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