Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens
Open accessAbstract
The S100A8/S100A9 heterodimer calprotectin (CP) functions in the host response to pathogens through a mechanism termed “nutritional immunity.” CP binds Mn 2+ and Zn 2+ with high affinity and starves bacteria of these essential nutrients. Combining biophysical, structural, and microbiological analysis, we identified the molecular basis of Mn 2+ sequestration. The asymmetry of the CP heterodimer creates a single Mn 2+ -binding site from six histidine residues, which distinguishes CP from all other Mn 2+ -binding proteins. Analysis of CP mutants with altered metal-binding properties revealed that, despite both Mn 2+ and Zn 2+ being essential metals, maximal growth inhibition of multiple bacterial pathogens requires Mn 2+ sequestration. These data establish the importance of Mn 2+ sequestration in defense against infection, explain the broad-spectrum antimicrobial activity of CP relative to other S100 proteins, and clarify the impact of metal depletion on the innate immune response to infection.
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Secreted calprotectin binds to and sequesters Zn, Mn, Ni and Fe in the extracellular milieu through the action of two metal-binding sites termed site I and site II that are formed at the S100A8-S100A9 interface.
“Secreted calpro tectin binds to and sequesters Zn, Mn, Ni and Fe in the extracellular milieu through the action of two metal- binding sites termed site I and site II that are formed at the S100A8-S100A9 interface 20,85,86 .”
From Nutritional immunity: the battle for nutrient metals at the host–pathogen interface (2022) · cites this paper as [85]
The section “Two Transition Metal-Binding Sites in CP Are Functionally Inequivalent” (page unavailable) supports Zn and Mn binding at two sites in the S100A8/S100A9 heterodimer, but explicitly reports that calprotectin does not bind iron. The passages found do not establish Ni sequestration. Thus the claim’s four-metal list conflicts with this source. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredCalprotectin-mediated manganese restriction causes maximum growth inhibition of bacteria.
“The central role of manganese starvation for anti-microbial activity has recently been underpinned by the finding that calprotectin-mediated manganese restriction causes maximum growth inhibition of bacteria (246).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [246]
The Mn2+-binding activity of calprotectin limits available manganese for many bacterial pathogens.
“The Mn2+-binding activity of calprotectin limits available manganese for many bacterial pathogens (32).”
From Transition Metals and Virulence in Bacteria (2016) · cites this paper as [32]
Calprotectin is an abundant neutrophil protein that chelates Zn2+ and Mn2+ and efficiently competes away these nutrient metals from numerous bacterial pathogens in vitro.
“Calprotectin is an abundant neutrophil protein that can chelate Zn2+ and Mn2+ and efficiently competes away these nutrient metals from numerous bacterial pathogens in vitro (32).”
From Transition Metals and Virulence in Bacteria (2016) · cites this paper as [32]
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Self-citationDietary Manganese Promotes Staphylococcal Infection of the Heart
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The Acinetobacter baumannii Znu System Overcomes Host-Imposed Nutrient Zinc Limitation
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Self-citationThe Immune Protein Calprotectin Impacts Clostridioides difficile Metabolism through Zinc Limitation
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Competition for Manganese at the Host–Pathogen Interface
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Self-citationRole of Metal Availability in Modulating Antibiotic Efficacy
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- Authors
- 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., Skaar, E. P., & Chazin, W. J.
- Affiliations
- Vanderbilt University (US)
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232-2363; and
- University of Freiburg (DE)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-02-19
- Volume
- 110
- Issue
- 10
- Pages
- 3841-3846
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3593839
- OpenAlex
- W1987816685
- Cited by
- 388
- References
- 57
- Citations by year
- 2026: 18 · 2025: 30 · 2024: 22 · 2023: 36 · 2022: 36 · 2021: 27 · 2020: 31 · 2019: 37 · 2018: 26 · 2017: 34 · 2016: 29 · 2015: 29 · 2014: 15 · 2013: 18
- FWCI
- 13.60
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32HL094296)
- National Institute of Mental Health (R01MH062122)
- National Cancer Institute (T32CA009582)
- National Institute of General Medical Sciences (R01 GM62122-S1)
- National Institute of Allergy and Infectious Diseases (R01AI069233, R56AI091771, R01AI073843, R01AI101171)
- National Institute of Environmental Health Sciences (P30ES000267)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Calpain Protease Function and Regulation
- Keywords
- calprotectin, zinc sequestration, nutritional immunity, innate immune response, pathogenic bacteria, metal-binding proteins, histidine residues, antimicrobial activity, metal depletion, host-pathogen interaction
- MeSH terms
- Binding Sites, Histidine, Humans, Immunity, Innate, Manganese, Models, Molecular, Recombinant Proteins, Staphylococcus aureus, Zinc, Mutagenesis, Site-Directed, Crystallography, X-Ray, Amino Acid Substitution, Leukocyte L1 Antigen Complex, Calgranulin A, Calgranulin B, Host-Pathogen Interactions, Protein Multimerization
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