The complement system labels microbes and host debris for clearance. Degradation of surface-bound C3b is pivotal to direct immune responses and protect host cells. How the serine protease factor I (FI), assisted by regulators, cleaves either two or three distant peptide bonds in the CUB domain of C3b remains unclear. We present a crystal structure of C3b in complex with FI and regulator factor H (FH; domains 1–4 with 19–20). FI binds C3b–FH between FH domains 2 and 3 and a reoriented C3b C-terminal domain and docks onto the first scissile bond, while stabilizing its catalytic domain for proteolytic activity. One cleavage in C3b does not affect its overall structure, whereas two cleavages unfold CUB and dislodge the thioester-containing domain (TED), affecting binding of regulators and thereby determining the number of cleavages. These data explain how FI generates late-stage opsonins iC3b or C3dg in a context-dependent manner, to react to foreign, danger or healthy self signals.

中文翻译：

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因子I对C3b加工的调控因子依赖性机制可区分免疫应答

补体系统标记微生物和宿主碎屑以清除。表面结合的C3b的降解对于指导免疫反应和保护宿主细胞至关重要。尚不清楚丝氨酸蛋白酶因子I（FI）如何在调节剂的辅助下切割C3b CUB结构域中的两个或三个远距离肽键。我们介绍了C3b的晶体结构，该结构与FI和调节因子H（FH； 19–20的1–4域）复合。FI在FH结构域2和3与重新定向的C3b C末端结构域之间结合C3b–FH，并停靠在第一个易裂键上，同时稳定其催化结构域的蛋白水解活性。C3b中的一次切割不影响其整体结构，而两次切割则使CUB折叠并移开含硫酯的结构域（TED），从而影响调节剂的结合，从而确定了切割的数量。