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Avian MRP126 Restricts Microbial Growth through Ca(II)-Dependent Zn(II) Sequestration.
Biochemistry ( IF 2.9 ) Pub Date : 2019-12-30 , DOI: 10.1021/acs.biochem.9b01012
Aaron T Bozzi 1 , Elizabeth M Nolan 1
Affiliation  

The calgranulins form a class of S100 proteins in higher vertebrates that innate-immune cells release in abundance at infection sites. These proteins function by binding transition metal ions to prevent microbial pathogens from obtaining those essential nutrients. Mammals express three distinct members of this family: S100A8 (calgranulin A), S100A9 (calgranulin B, which heterooligomerizes with S100A8 to form calprotectin), and S100A12 (calgranulin C), that exhibit Ca(II)-dependent transition metal binding properties. Human calprotectin effectively sequesters Mn(II), Fe(II), Ni(II), and Zn(II), whereas human S100A12 selectively sequesters Zn(II) over these other metal ions. Birds and reptiles express a single calgranulin homologue named MRP126, which we reasoned could have properties more similar to those of either calprotectin or S100A12. Here we present the purification and biophysical characterization of recombinant chicken MRP126 and, to the best of our knowledge, provide the first assessment of the metal binding and antimicrobial properties of an avian MRP126. We show that MRP126 is a homodimer that selectively sequesters Zn(II) and restricts the growth of certain microbes. MRP126 binds Zn(II) at two canonical His3Asp sites. The presence of excess Ca(II) increases the affinity of the His3Asp sites from the low-nanomolar to the low-picomolar range, thereby enhancing antimicrobial activity. Chicken MRP126 also binds additional Zn(II) equivalents with low-nanomolar affinity at two nonconserved dicysteine sites and with high-nanomolar affinity using a histidine-rich C-terminal tail that is a hallmark of this clade of calgranulins. Our results with chicken MRP126 suggest that Ca(II)-dependent Zn(II) sequestration was a role of the last common ancestor of calgranulin proteins, with mammalian calprotectin subsequently evolving a broader metal binding repertoire.

中文翻译:

禽MRP126通过依赖Ca(II)的Zn(II)隔离来限制微生物的生长。

钙粘蛋白在高级脊椎动物中形成一类S100蛋白,其先天免疫细胞在感染部位大量释放。这些蛋白质通过结合过渡金属离子而起作用,以防止微生物病原体获得那些必需的营养素。哺乳动物表达了这个家族的三个不同成员:S100A8(钙粒蛋白A),S100A9(钙粒蛋白B,与S100A8杂聚形成钙卫蛋白)和S100A12(钙粒蛋白C),它们具有Ca(II)依赖性过渡金属结合特性。人钙卫蛋白可以有效地隔离Mn(II),Fe(II),Ni(II)和Zn(II),而人S100A12可以选择性地隔离Zn(II)覆盖这些其他金属离子。鸟类和爬行动物表达的是一个单一的钙网蛋白同系物,名为MRP126,我们认为它的性质可能与钙卫蛋白或S100A12相似。在这里,我们介绍重组鸡MRP126的纯化和生物物理特性,并据我们所知,对禽类MRP126的金属结合和抗菌特性进行了首次评估。我们表明,MRP126是同型二聚体,选择性螯合Zn(II)并限制某些微生物的生长。MRP126在两个规范的His3Asp位点结合Zn(II)。过量Ca(II)的存在增加了His3Asp位点从低纳摩尔到低皮摩尔范围的亲和力,从而增强了抗菌活性。鸡MRP126还使用富含组氨酸的C末端尾巴结合了这两个钙网蛋白的标志物,在两个非保守的半胱氨酸位点以低纳摩尔亲和力与高纳摩尔亲和力结合了其他的Zn(II)等效物。
更新日期:2020-01-22
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