4.8 Article

The Hexahistidine Motif of Host-Defense Protein Human Calprotectin Contributes to Zinc Withholding and Its Functional Versatility

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JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 138, 期 37, 页码 12243-12251

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AMER CHEMICAL SOC
DOI: 10.1021/jacs.6b06845

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资金

  1. NSF [CHE-1352132]
  2. NIH [DP2OD007045]
  3. Camille and Henry Dreyfus Foundation
  4. Alfred P. Sloan Foundation
  5. NSF
  6. Canada Foundation for Innovation
  7. Natural Sciences and Engineering Research Council of Canada
  8. University of Saskatchewan
  9. Government of Saskatchewan
  10. Western Economic Diversification Canada
  11. National Research Council Canada
  12. Canadian Institutes of Health Research
  13. [NSF-0070319]
  14. Direct For Mathematical & Physical Scien
  15. Division Of Chemistry [1352132, 1362662] Funding Source: National Science Foundation

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Human calprotectin (CP, S100A8/S100A9 oligomer, MRP-8/MRP-14 oligomer) is an abundant host-defense protein that is involved in the metal-withholding innate immune response. CP coordinates a variety of divalent first-row transition metal ions, which is implicated in its antimicrobial function, and its ability to sequester nutrient Zn(II) ions from microbial pathogens has been recognized for over two decades. CP has two distinct transition-metal-binding sites formed at the S100A8/S100A9 dimer interface, including a histidine-rich site composed of S100A8 residues His17 and His27 and S100A9 residues His91 and His95. In this study, we report that CP binds Zn(II) at this site using a hexahistidine motif, completed by His103 and His105 of the S100A9 C-terminal tail and previously identified as the high-affinity Mn(II) and Fe(II) coordination site. Zn(II) binding at this unique site shields the S100A9 C-terminal tail from proteolytic degradation by proteinase K. X-ray absorption spectroscopy and Zn(II) competition titrations support the formation of a Zn(II)-His(6) motif. Microbial growth studies indicate that the hexahistidine motif is important for preventing microbial Zn(II) acquisition from CP by the probiotic Lactobacillus plantarum and the opportunistic human pathogen Candida albicans. The Zn(II)-His(6) site of CP expands the known biological coordination chemistry of Zn(II) and provides new insight into how the human innate immune system starves microbes of essential metal nutrients.

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