期刊
BIOCHEMISTRY
卷 57, 期 28, 页码 4155-4164出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.8b00415
关键词
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资金
- National Science Foundation [CHE-1352132]
- National Institutes of Health (NIH) [R01GM126376, R01GM118695, R01GM069857, F32-GM099257]
- MIT Center for Environmental Health Sciences (NIH) [P30-ES002109]
- MIT Center for Environmental Health Sciences Theron Randolph Gift
- National Science Foundation Graduate Research Fellowship Program
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR029205] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [P30ES002109] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM069857, R01GM126376, R01GM118695, F32GM099257, P41GM103403] Funding Source: NIH RePORTER
Calprotectin (CP, S100A8/S100A9 oligomer, MRP-8/MRP-14 oligomer) is a host-defense protein that sequesters nutrient transition metals from microbes. Each S100A8/S100A9 heterodimer contains four EF-hand domains and two transition-metal-binding sites. We investigate the effect of Ca(II) ions on the structure and Ni(II)-binding properties of human CP. By employing energy dispersive X-ray EDX) spectroscopy, we evaluate the metal content of Ni(II)-bound CP-Ser [oligomer of S100A8(C42S) and S100A9(C3S)] crystals obtained in the absence and presence of Ca(II). We present a 2.1 angstrom resolution crystal structure of Ni(II)-bound CP-Ser and compare this structure to a reported Ni(II)- and Ca(II)-bound CP-Ser structure [Nakashige, T. G., et al. (2017) J. Am. Chem. Soc. 139, 8828-8836]. This analysis reveals conformational changes associated with coordination of Ca(II) to the EF-hands of S100A9 and that Ca(II) binding affects the coordination number and geometry of the Ni(II) ion bound to the His(3)Asp site. In contrast, negligible differences are observed for the Ni(II)-His(6) site in the absence and presence of Ca(II). Biochemical studies show that, whereas the His(6) site has a thermodynamic preference for Ni(II) over Zn(II), the His(3)Asp site selects for Zn(II) over Ni(II), and relatively rapid metal exchange occurs at this site. These observations inform the working model for how CP withholds nutrient metals in the extracellular space.
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