Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens
Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens
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DOI：
10.1073/pnas.1220341110
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发表时间：
2013-03-05
影响因子：
11.1
通讯作者：
Chazin, Walter J.
中科院分区：
文献类型：
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作者：
Damo, Steven M.;Kehl-Fie, Thomas E.;Chazin, Walter J.
S100 A8/S100 A9异二聚体钙卫蛋白（CP）通过称为“营养免疫”的机制在宿主对病原体的反应中发挥作用。“CP以高亲和力结合Mn 2+和Zn 2+，使细菌缺乏这些必需的营养素。结合生物物理，结构和微生物分析，我们确定了Mn 2+螯合的分子基础。CP异二聚体的不对称性从六个组氨酸残基中产生了一个单一的Mn 2+结合位点，这将CP与所有其他Mn 2+结合蛋白区分开来。CP突变体与改变金属结合特性的分析表明，尽管Mn 2+和Zn 2+是必需的金属，最大限度地抑制多种细菌病原体的生长需要Mn 2+螯合。这些数据确立了Mn 2+螯合在防御感染中的重要性，解释了CP相对于其他S100蛋白的广谱抗微生物活性，并阐明了金属耗竭对感染的先天免疫反应的影响。
The S100A8/S100A9 heterodimer calprotectin (CP) functions in the host response to pathogens through a mechanism termed "nutritional immunity." CP binds Mn2+ and Zn2+ with high affinity and starves bacteria of these essential nutrients. Combining biophysical, structural, and microbiological analysis, we identified the molecular basis of Mn2+ sequestration. The asymmetry of the CP heterodimer creates a single Mn2+-binding site from six histidine residues, which distinguishes CP from all other Mn2+-binding proteins. Analysis of CP mutants with altered metal-binding properties revealed that, despite both Mn2+ and Zn2+ being essential metals, maximal growth inhibition of multiple bacterial pathogens requires Mn2+ sequestration. These data establish the importance of Mn2+ sequestration in defense against infection, explain the broad-spectrum antimicrobial activity of CP relative to other S100 proteins, and clarify the impact of metal depletion on the innate immune response to infection.