Nickel Sequestration by the Host-Defense Protein Human Calprotectin
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Author(s)
Nakashige, Toshiki George
Zygiel, Emily Mikayla
Drennan, Catherine L
Nolan, Elizabeth Marie
Date Issued
July 2017
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Citation
Nakashige, Toshiki G. et al. “Nickel Sequestration by the Host-Defense Protein Human Calprotectin.” Journal of the American Chemical Society 139, 26 (June 2017): 8828–8836 © 2017 American Chemical Society
Version
Author's final manuscript
Abstract
The human innate immune protein calprotectin (CP, S100A8/S100A9 oligomer, calgranulin A/calgranulin B oligomer, MRP-8/MRP-14 oligomer) chelates a number of first-row transition metals, including Mn(II), Fe(II), and Zn(II), and can withhold these essential nutrients from microbes. Here we elucidate the Ni(II) coordination chemistry of human CP. We present a 2.6-Å crystal structure of Ni(II)- and Ca(II)-bound CP, which reveals that CP binds Ni(II) ions at both its transition-metal-binding sites: the His3Asp motif (site 1) and the His6motif (site 2). Further biochemical studies establish that coordination of Ni(II) at the hexahistidine site is thermodynamically preferred over Zn(II). We also demonstrate that CP can sequester Ni(II) from two human pathogens, Staphylococcus aureus and Klebsiella pneumoniae, that utilize this metal nutrient during infection, and inhibit the activity of the Ni(II)-dependent enzyme urease in bacterial cultures. In total, our findings expand the biological coordination chemistry of Ni(II)-chelating proteins in nature and provide a foundation for evaluating putative roles of CP in Ni(II) homeostasis at the host-microbe interface and beyond.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1021/JACS.7B01212
