Nakashige Toshiki G, Zhang Bo, Krebs Carsten, Nolan Elizabeth M
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania, USA.
Nat Chem Biol. 2015 Oct;11(10):765-71. doi: 10.1038/nchembio.1891. Epub 2015 Aug 24.
Human calprotectin (CP) is a metal-chelating antimicrobial protein of the innate immune response. The current working model states that CP sequesters manganese and zinc from pathogens. We report the discovery that CP chelates iron and deprives bacteria of this essential nutrient. Elemental analysis of CP-treated growth medium establishes that CP reduces the concentrations of manganese, iron and zinc. Microbial growth studies reveal that iron depletion by CP contributes to the growth inhibition of bacterial pathogens. Biochemical investigations demonstrate that CP coordinates Fe(II) at an unusual hexahistidine motif, and the Mössbauer spectrum of (57)Fe(II)-bound CP is consistent with coordination of high-spin Fe(II) at this site (δ = 1.20 mm/s, ΔEQ = 1.78 mm/s). In the presence of Ca(II), CP turns on its iron-sequestering function and exhibits subpicomolar affinity for Fe(II). Our findings expand the biological coordination chemistry of iron and support a previously unappreciated role for CP in mammalian iron homeostasis.
人钙卫蛋白（CP）是先天性免疫反应中的一种金属螯合抗菌蛋白。目前的工作模型表明，CP从病原体中螯合锰和锌。我们报告发现CP螯合铁并使细菌缺乏这种必需营养素。对CP处理过的生长培养基进行元素分析表明，CP降低了锰、铁和锌的浓度。微生物生长研究表明，CP导致的铁耗竭有助于抑制细菌病原体的生长。生化研究表明，CP在一个不寻常的六组氨酸基序处配位Fe（II），并且（57）Fe（II）结合的CP的穆斯堡尔谱与此处高自旋Fe（II）的配位一致（δ = 1.20 mm/s，ΔEQ = 1.78 mm/s）。在Ca（II）存在的情况下，CP开启其铁螯合功能并对Fe（II）表现出亚皮摩尔亲和力。我们的发现扩展了铁的生物配位化学，并支持了CP在哺乳动物铁稳态中以前未被认识到的作用。
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