Interdependence of Antimicrobial and Pro-inflammatory Activities Mediated by S100A12 in the Innate Immune Response

在病原体入侵期间，关键营养素（如Zn（II）、Fe（II）和Mn（II））的螯合是一种重要的生物学过程。 宿主细胞为阻止感染而采取的共同策略。在人类中，这项任务是由一个子集， Ca（II）结合S100蛋白如S100 A12。通过在其二聚体界面处螯合Zn（II），S100 A12执行 抗菌活性。在感染过程中，S100 A12与膜受体相互作用，例如用于 晚期糖基化终末产物（AGEs）以启动促炎信号级联。虽然已知 参与抗微生物和促炎活性，S100 A12与 启动炎症信号传导的膜受体是未知的。我们的研究计划设想 研究S100 A12的分子水平的相互作用，从而引发炎症途径。 我们最近报道的研究已经确定了S100 A12的几个关键特征，例如（i） 蛋白质形成主要由Zn（II）结合主导的可逆寡聚组装体;（ii）Zn（II）连接 将构象变化引入蛋白质的功能相关结构域;和（iii）调节 在生理相关pH条件下通过Ca（II）螯合Zn（II）。这些结果，沿着以前的 文献中报道的研究表明，在炎症部位存在寡聚体S100 A12， 已经奠定了我们的假设的基础，该假设提出了金属结合介导的串扰， S100 A12的抗微生物和炎症功能。我们的研究计划将进行一项生物物理学研究， 研究S100 A12在免疫应答中发挥作用的分子水平相互作用的方法。 针对二价金属离子（Ca（II）和Zn（II））的结合及其对S100 A12功能的影响，我们提出 下面的具体目标来测试我们的假设：（i）钙诱导的结构，动力学和 功能;（ii）二价金属离子介导的S100 A12信号转导;和（iii）S100 A12的分子基础 炎症反应中的相互作用。 这些拟议的研究将集中在Ca（II）和Zn（II）结合到原子和分子水平的作用上。 详细评估影响S100 A12-膜传感器体外相互作用的因素。我们的调查结果显示， 预期工作将为类似的免疫系统组分的整体功能提供框架， 允许开发免疫应答的通用模型。最后，这项工作也是预期的。 产生的信息可以帮助开发有效的治疗靶向分子，如S100 A12， 异常炎症

Sequestration of critical nutrients (such as Zn(II), Fe(II) and Mn(II)) during pathogenic invasion is a common strategy undertaken by host cells to thwart infection. In humans, this task is performed by a subset of Ca(II) binding S100 proteins such as S100A12. By chelating Zn(II) at its dimeric interface, S100A12 performs antimicrobial activities. During infection, S100A12 interacts with membrane receptors such as the receptor for advanced glycation end products (RAGE) to initiate a pro-inflammatory signaling cascade. Although known to participate in both antimicrobial and pro-inflammatory activities, the mode of interaction of S100A12 with membrane receptors that initiates inflammatory signaling, is not known. Our research program envisions investigating molecular-level interactions of S100A12 that instigate inflammatory pathways. Our recently reported studies have identified several key features of S100A12 such as (i) the ability of the protein to form reversible oligomeric assemblies that is mostly dominated by Zn(II) binding; (ii) Zn(II) ligation introduced conformational changes to functionally relevant domains of the protein and; (iii) the modulation of Zn(II) sequestration by Ca(II) at physiologically relevant pH conditions. These results, along with previously reported studies in the literature demonstrating the presence of oligomeric S100A12 at inflammatory sites in vivo have laid the foundation of our hypothesis which proposes a metal binding mediated crosstalk between antimicrobial and inflammatory functions of S100A12. Our research program will undertake a biophysical approach to investigate molecular level interactions of S100A12 that afford its functions in the immune response. Focusing on divalent metal ion (Ca(II) and Zn(II)) binding and their influence on S100A12 functions, we propose the following specific aims to test our hypothesis: (i) calcium induced regulation of structure, dynamics and functions; (ii) divalent metal ion mediated signal transduction by S100A12; and (iii) molecular basis of S100A12 interactions in inflammatory responses. These proposed studies will focus on the role of Ca(II) and Zn(II) binding to atomic- and molecular-level details to evaluate the factors influencing S100A12-membrane sensor interactions in vitro. The findings of our work are expected to provide a framework for overall functioning of similar immune system components, allowing for the development of a generalized model of the immune response. Lastly, this work is also expected to generate information that could help develop efficient therapeutic targeting molecules such as S100A12 during aberrant inflammation.