The structural basis of alternative pathway initiation

The alternative complement pathway (AP) is a crucial part of the human innate immune system and is in first line of defence against invading pathogens. The AP is solicited by pathogen proteins which often interact with human complement factor 3 (C3), the central hub of the complement cascade. This interaction is sufficient to block progression of the complement cascade. Within the AP, the first step of activation involves the conversion of C3 into C3(H2O) which forms the fluid-phase convertase. The aim of the proposal is to resolve for the first time the structure of intact C3(H2O) at near-atomic resolution. Previously we obtained a preliminary structure of C3(H2O) with a small data set at low resolution. The high-resolution structure of C3(H20) will inform about the conformational changes that occur upon cleavage of the thioester bond while the ANA domain (C3a when released) is still being present.

补体旁路途径（alternative complement pathway, AP）是人类先天免疫系统的关键组成部分，亦是抵御入侵病原体的第一道防线。该途径可由病原体蛋白触发激活，此类蛋白通常会与补体级联反应的核心枢纽——人类补体因子3（complement factor 3, C3）相结合，此种结合足以阻断补体级联反应的进程。在补体旁路途径中，激活的第一步是将C3转化为C3(H2O)，进而形成液相转化酶。本研究提案的目标是首次解析完整C3(H2O)的近原子分辨率结构。此前我们曾利用小型数据集获得了低分辨率的C3(H2O)初步结构。C3(H2O)的高分辨率结构将阐明：当硫酯键发生断裂，且ANA结构域（释放后即为C3a）仍保留于分子中时，所发生的构象变化。