Human calprotectin (CP) is a metal-sequestering protein of the innate immune system that displays remarkable coordination chemistry.  The apo protein is released into the extracellular space where it inhibits the growth of microbial pathogens by chelating first-row transition metal ions, thereby limiting the availability of essential nutrients. CP is a heterooligomer of two Ca(II)-binding S100 polypeptides, S100A8 and S100A9. In addition to Ca(II)-binding EF-hand domains, each S100A8/S100A9 heterodimer exhibits two sites for transition metal binding at the dimer interface, a His₃Asp site and a His₆ site. The His₆ site provides CP with functional versatility because it entraps divalent first-row transition metal ions that include Mn(II), Fe(II), Ni(II) and Zn(II). In contrast, the His₃Asp site is effective at sequestering Zn(II). Select vignettes from recent  biochemical, biophysical and functional studies of CP that inform the working model for how CP withholds metal nutrients in the extracellular space will first be presented. In particular, we will examine CP in the context of iron withholding by the innate immune system. 

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