Human calprotectin is an iron-sequestering host-defense protein

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 [superscript 57]Fe(II)-bound CP is consistent with coordination of high-spin Fe(II) at this site (δ = 1.20 mm/s, ΔE[subscript Q] = 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.National Institutes of Health (U.S.) (NIH grant 1DP2OD007045)Alfred P. Sloan FoundationKinship Foundation (Searle Scholars Program award)National Institutes of Health (U.S.) (MIT Center for Environmental Health Sciences (NIH P30-ES002109))National Science Foundation (U.S.) (NSF Graduate Research Fellowship