Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
J Biol Chem. 2013 Jun 28;288(26):18789-802. doi: 10.1074/jbc.M112.420331. Epub 2013 Apr 26.
Molecules that simultaneously inhibit independent or co-dependent proinflammatory pathways may have advantages over conventional monotherapeutics. OmCI is a bifunctional protein derived from blood-feeding ticks that specifically prevents complement (C)-mediated C5 activation and also sequesters leukotriene B4 (LTB4) within an internal binding pocket. Here, we examined the effect of LTB4 binding on OmCI structure and function and investigated the relative importance of C-mediated C5 activation and LTB4 in a mouse model of immune complex-induced acute lung injury (IC-ALI). We describe two crystal structures of bacterially expressed OmCI: one binding a C16 fatty acid and the other binding LTB4 (C20). We show that the C5 and LTB4 binding activities of the molecule are independent of each other and that OmCI is a potent inhibitor of experimental IC-ALI, equally dependent on both C5 inhibition and LTB4 binding for full activity. The data highlight the importance of LTB4 in IC-ALI and activation of C5 by the complement pathway C5 convertase rather than by non-C proteases. The findings suggest that dual inhibition of C5 and LTB4 may be useful for treatment of human immune complex-dependent diseases.
同时抑制独立或共同依赖的促炎途径的分子可能比传统的单疗法具有优势。OmCI 是一种来源于吸血蜱的双功能蛋白，它能特异性地阻止补体（C）介导的 C5 激活，同时将白三烯 B4（LTB4）封闭在内部结合口袋内。在这里，我们研究了 LTB4 结合对 OmCI 结构和功能的影响，并在免疫复合物诱导的急性肺损伤（IC-ALI）的小鼠模型中研究了 C 介导的 C5 激活和 LTB4 的相对重要性。我们描述了两种细菌表达的 OmCI 的晶体结构：一种与 C16 脂肪酸结合，另一种与 LTB4（C20）结合。我们表明，该分子的 C5 和 LTB4 结合活性彼此独立，并且 OmCI 是实验性 IC-ALI 的有效抑制剂，其完全活性既依赖于 C5 抑制，也依赖于 LTB4 结合。这些数据强调了 LTB4 在 IC-ALI 中的重要性，以及补体途径 C5 转化酶而非非 C 蛋白酶激活 C5 的作用。这些发现表明，同时抑制 C5 和 LTB4 可能对治疗人类免疫复合物依赖性疾病有用。
