The interaction between pathogenic microbes and their host is mediated by the bioavailability of essential nutrients such as transition metals. An important immune response in humans is the ability to sequester metals, depriving the infecting pathogen from access to the nutrients, which can in turn impair bacterial growth. Here we present the X-ray crystal structure of human calprotectin, a protein that functions to scavenge transition metals, depleting the bioavailable supply for use by pathogens. Calprotectin is a heterodimer composed of two S100 family proteins (S100A8 and S100A9). The structure of calprotectin (obtained to 1.76 Å resolution) reveals a biologically unprecedented coordination site for Mn(II), with six coordinating His residues symmetrically arranged at the dimer interface [1,2]. Additionally, we observe two Ca(II) ions in the canonical S100 EF-hand domains, and use anomalous electron density to rule out Ca(II)-binding in the non-canonical S100 EF-hand domains for these crystallization conditions. We hypothesize about the physiological role of Ca(II)-binding in calprotectin to enhance affinity for transition metals, and speculate about the number of Ca(II) ions required for this increased affinity. 1. Gagnon, DM, et al. JACS 2015, 137, 3004. 2. Damo, SM, et al. PNAS 2013, 100, 3841.

Crystallographic studies of the immune-response, metal chelating protein calprotectin

250th National Meeting (2015)

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