Human calprotectin is an iron-sequestering host-defense protein

Toshiki G. Nakashige, Bo Zhang, Carsten Krebs, Elizabeth M. Nolan

Research output: Contribution to journalArticlepeer-review

191 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)765-771
Number of pages7
JournalNature Chemical Biology
Issue number10
StatePublished - Oct 19 2015

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


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