Human calprotectin is an iron-sequestering host-defense protein

Nat Chem Biol. 2015 Oct;11(10):765-71. doi: 10.1038/nchembio.1891. Epub 2015 Aug 24.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Calcium / chemistry
  • Calcium / metabolism
  • Electron Spin Resonance Spectroscopy
  • Escherichia coli / drug effects
  • Escherichia coli / growth & development
  • Escherichia coli / metabolism*
  • Host-Pathogen Interactions* / physiology
  • Humans
  • Iron / metabolism*
  • Iron Chelating Agents / metabolism
  • Iron Chelating Agents / pharmacology*
  • Lactobacillus plantarum / drug effects
  • Lactobacillus plantarum / growth & development
  • Lactobacillus plantarum / metabolism
  • Leukocyte L1 Antigen Complex / genetics
  • Leukocyte L1 Antigen Complex / pharmacology*
  • Leukocyte L1 Antigen Complex / physiology
  • Microbial Sensitivity Tests
  • Spectroscopy, Mossbauer
  • Staphylococcus aureus / drug effects
  • Staphylococcus aureus / growth & development
  • Staphylococcus aureus / metabolism*


  • Iron Chelating Agents
  • Leukocyte L1 Antigen Complex
  • Iron
  • Calcium