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Structure of C3b reveals conformational changes that underlie complement activity

机译：C3b的结构揭示了补体活性基础的构象变化

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摘要

Resistance to infection and clearance of cell debris in mammals depend on the activation of the complement system, which is an important component of innate and adaptive immunity(1,2). Central to the complement system is the activated form of C3, called C3b, which attaches covalently to target surfaces(3) to amplify complement response, label cells for phagocytosis and stimulate the adaptive immune response. C3b consists of 1,560 amino-acid residues and has 12 domains. It binds various proteins and receptors to effect its functions(4). However, it is not known how C3 changes its conformation into C3b and thereby exposes its many binding sites. Here we present the crystal structure at 4-angstrom resolution of the activated complement protein C3b and describe the conformational rearrangements of the 12 domains that take place upon proteolytic activation. In the activated form the thioester is fully exposed for covalent attachment to target surfaces and is more than 85 angstrom away from the buried site in native C3 (ref. 5). Marked domain rearrangements in the alpha-chain present an altered molecular surface, exposing hidden and cryptic sites that are consistent with known putative binding sites of factor B and several complement regulators. The structural data indicate that the large conformational changes in the proteolytic activation and regulation of C3 take place mainly in the first conversion step, from C3 to C3b. These insights are important for the development of strategies to treat immune disorders that involve complement-mediated inflammation.
机译：哺乳动物对感染和细胞碎片清除的抵抗力取决于补体系统的激活，这是先天和适应性免疫的重要组成部分（1,2）。补体系统的中心是C3的活化形式，称为C3b，它共价附于靶表面（3）以放大补体应答，标记细胞吞噬作用并刺激适应性免疫应答。 C3b由1,560个氨基酸残基组成，并具有12个域。它结合各种蛋白质和受体以影响其功能（4）。但是，尚不知道C3如何将其构象改变为C3b，从而暴露出其许多结合位点。在这里，我们介绍了激活的补体蛋白C3b在4埃分辨率下的晶体结构，并描述了蛋白水解激活后发生的12个结构域的构象重排。在活化形式下，硫酯完全暴露出来以与目标表面共价结合，并且与天然C3中的掩埋位相距超过85埃（参考文献5）。 α链中标记的结构域重排呈现改变的分子表面，暴露出与因子B和几种补体调节剂的已知推定结合位点一致的隐藏和隐蔽位点。结构数据表明，C3的蛋白水解激活和调节中的构象变化较大，主要发生在从C3到C3b的第一个转化步骤中。这些见解对于制定治疗涉及补体介导的炎症的免疫疾病的策略非常重要。

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