Department of Infection, University of Leicester, Leicester LE1 9HN, United Kingdom.
Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13916-20. doi: 10.1073/pnas.1311113110. Epub 2013 Aug 6.
Complement component C1, the complex that initiates the classical pathway of complement activation, is a 790-kDa assembly formed from the target-recognition subcomponent C1q and the modular proteases C1r and C1s. The proteases are elongated tetramers that become more compact when they bind to the collagen-like domains of C1q. Here, we describe a series of structures that reveal how the subcomponents associate to form C1. A complex between C1s and a collagen-like peptide containing the C1r/C1s-binding motif of C1q shows that the collagen binds to a shallow groove via a critical lysine side chain that contacts Ca(2+)-coordinating residues. The data explain the Ca(2+)-dependent binding mechanism, which is conserved in C1r and also in mannan-binding lectin-associated serine proteases, the serine proteases of the lectin pathway activation complexes. In an accompanying structure, C1s forms a compact ring-shaped tetramer featuring a unique head-to-tail interaction at its center that replicates the likely arrangement of C1r/C1s polypeptides in the C1 complex. Additional structures reveal how C1s polypeptides are positioned to enable activation by C1r and interaction with the substrate C4 inside the cage-like assembly formed by the collagenous stems of C1q. Together with previously determined structures of C1r fragments, the results reported here provide a structural basis for understanding the early steps of complement activation via the classical pathway.
补体成分 C1 是补体经典激活途径的起始复合物，由靶识别亚基 C1q 和模块化蛋白酶 C1r 和 C1s 组成，分子量为 790kDa。蛋白酶是伸长的四聚体，与 C1q 的胶原样结构域结合时变得更加紧凑。在这里，我们描述了一系列结构，揭示了亚基如何组装形成 C1。C1s 与含有 C1q 的 C1r/C1s 结合基序的胶原样肽之间的复合物表明，胶原通过与 Ca(2+)配位残基结合的关键赖氨酸侧链结合到浅沟中。该数据解释了 Ca(2+)依赖性结合机制，该机制在 C1r 中以及甘露聚糖结合凝集素相关丝氨酸蛋白酶（凝集素途径激活复合物的丝氨酸蛋白酶）中保守。在一个伴随的结构中，C1s 形成一个紧凑的环形四聚体，其中心具有独特的头对头相互作用，复制了 C1 复合物中 C1r/C1s 多肽的可能排列。其他结构揭示了 C1s 多肽如何定位，以实现 C1r 的激活以及与笼状组装内的底物 C4 的相互作用，该组装由 C1q 的胶原样茎形成。与先前确定的 C1r 片段结构相结合，这里报道的结果为理解通过经典途径激活补体的早期步骤提供了结构基础。
