Metals and Immunity

Abstract:

The global public health problems of infectious disease and antibiotic resistance motivate our bioinorganic investigations of the host/pathogen interaction. Metal ions are essential nutrients for all organisms, and metal-ion withholding is one accepted mechanism of innate immunity. Inspired
by the structures and biological functions of human host-defense proteins that participate in this metal-ion withholding response, we aim to achieve molecular-level and quantitative depictions of how these biomolecules contribute to innate immunity, metal homeostasis, and physiology. In one
thrust, we are investigating the metal-sequestering antimicrobial protein calprotectin. This host- defense protein is released by neutrophils and epithelial cells, and exerts antimicrobial activity attributed to its ability to sequester transition metals from microbes. Our central hypotheses are that calprotectin (i) contributes to human physiology in multiple contexts, (ii) responds to local environmental stimuli and thereby exists in multiple structural forms that have particular physiological roles, and (iii) participates in the homeostasis of metals in broad terms. Here, we describe our bioinorganic studies of human calprotectin, which reveal remarkable biological coordination chemistry essential for its function as an antimicrobial agent. Each calprotectin heterodimer exhibits six distinct metal-binding sites, and we report our discovery that calprotectin employs Ca(II) ions to tune its affinity for first-row transition metal ions. This mechanism allows for calprotectin to switch between relatively low and high affinity forms, and effectively turn on its metal-sequestering function in the extracellular space where Ca(II) levels are high. We also focus on our studies of Fe(II) chelation by calprotectin, which suggest that this protein has the capacity to contribute to iron homeostasis under reducing and anaerobic conditions where iron persists in the ferrous oxidation state.