The S100A8/S100A9 heterodimer calprotectin, comprising 40-50% of the protein component of neutrophil cytoplasm, is an important factor in vertebrate innate immune response to infection. Zinc and manganese bind with high affinity to two distinct transition metal binding sites in calprotectin in 2:1 and 1:1 metal to protein ratios respectively. To elucidate the relationship between metal chelation and bacterial growth suppression, the structural basis for transition metal chelation by calprotectin was examined and correlated with inhibition of S. aureus growth by calprotectin. Isothermal titration calorimetry (ITC) analysis revealed that, while both sites bind to zinc, only Site I binds manganese with high affinity. Disruption of either Site I or Site II increased the IC50 against S. aureus by twofold as compared to wild type calprotectin. The Site I variant exhibited increased antimicrobial activity as compared to the Site I variant, revealing a ritical role for manganese sequestration in calprotectin's antimicrobial activity.

Identification of the zinc and manganese binding sites in calprotectin and their role in host defense against <i>Staphylococcus</i> <i>aureus</i>

243rd National Meeting (2012)

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Identification of the zinc and manganese binding sites in calprotectin and their role in host defense against Staphylococcus aureus