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

在病原体入侵期间，关键营养物质(如锌(II)、铁(II)和锰(II))的隔离是 宿主细胞为阻止感染而采取的共同策略。在人类中，这项任务是由以下部分执行的 CA(II)结合S100蛋白，如S100A12。通过在其二聚体界面上螯合锌(II)，S100A12表现出 抗菌活性。在感染过程中，S100A12与膜受体相互作用，如 晚期糖基化终末产物(RAGE)启动促炎信号级联反应。虽然大家都知道 同时参与抗菌和促炎活性，S100A12与 启动炎症信号的膜受体尚不清楚。我们的研究计划设想 研究S100A12引发炎症途径的分子水平的相互作用。 我们最近报道的研究已经确定了S100A12的几个关键特征，例如：(I) 蛋白质形成以锌(II)结合为主的可逆寡聚体；(Ii)锌(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 在生理相关的pH条件下，Ca(II)对锌(II)的固着作用。这些结果，以及之前的 文献报道的研究表明，在炎症部位存在寡聚体S100A12。 Vivo已经为我们的假设奠定了基础，该假设提出了金属结合介导的串扰 S100A12的抗菌和抗炎作用。我们的研究计划将进行生物物理 研究S100A12在免疫应答中的分子水平相互作用。 针对二价金属离子(Ca(II)和Zn(II))的结合及其对S100A12功能的影响，我们提出了 以下具体目的是为了验证我们的假设：(I)钙诱导的结构、动力学和 S100A12的功能；(Ii)二价金属离子介导的信号转导；(Iii)S100A12的分子基础 炎症反应中的相互作用。 这些拟议的研究将侧重于钙(II)和锌(II)结合在原子和分子水平上的作用 详细评价影响S100A12与膜传感器相互作用的体外因素。我们的调查结果是 预计这项工作将为类似免疫系统组件的整体功能提供一个框架， 从而发展出一种免疫反应的通用模型。最后，对本文的工作也进行了展望 产生可帮助开发有效的治疗靶向分子的信息，如S100A12 反常炎症。

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.