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首页> 外文期刊>Journal of Molecular Biology >The structure of bovine complement component 3 reveals the basis for thioester function.
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The structure of bovine complement component 3 reveals the basis for thioester function.

机译：牛补体成分3的结构揭示了硫酯功能的基础。

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摘要

The third component of complement (C3) is a 190 kDa glycoprotein essential for eliciting the complement response. The protein consists of two polypeptide chains (alpha and beta) held together with a single disulfide bridge. The beta-chain is composed of six MG domains, one of which is shared with the alpha-chain. The disulfide bridge connecting the chains is positioned in the shared MG domain. The alpha-chain consists of the anaphylatoxin domain, three MG domains, a CUB domain, an alpha(6)/alpha(6)-barrel domain and the C-terminal C345c domain. An internal thioester in the alpha-chain of C3 (present in C4 but not in C5) is cleaved during complement activation. This mediates covalent attachment of the activated C3b to immune complexes and invading microorganisms, thereby opsonizing the target. We present the structure of bovine C3 determined at 3 Angstroms resolution. The structure shows that the ester is buried deeply between the thioester domain and the properdin binding domain, in agreement with the human structure. This domain interface is broken upon activation, allowing nucleophile access. The structure of bovine C3 clearly demonstrates that the main chain around the thioester undergoes a helical transition upon activation. This rearrangement is proposed to be the basis for the high level of reactivity of the thioester group. A strictly conserved glutamate residue is suggested to function catalytically in thioester proteins. Structure-based design of inhibitors of C3 activation may target a conserved pocket between the alpha-chain and the beta-chain of C3, which appears essential for conformational changes in C3.
机译：补体（C3）的第三个成分是190 kDa的糖蛋白，对引发补体反应至关重要。该蛋白质由两条多肽链（α和β）和一条二硫键连接在一起。 beta链由六个MG域组成，其中一个域与alpha链共享。连接链的二硫键位于共享的MG域中。 α链由过敏毒素域，三个MG域，CUB域，α（6）/ alpha（6）-桶形域和C端C345c域组成。在补体激活过程中，C3的α链（存在于C4中，但不存在于C5中）的内部硫酯被裂解。这介导了活化的C3b与免疫复合物和入侵微生物的共价结合，从而调理了靶标。我们介绍了在3埃分辨率下确定的牛C3的结构。结构表明，该酯与人的结构一致，被深深地埋在硫酯结构域和备解素结合结构域之间。该域接口在激活时被破坏，允许亲核试剂访问。牛C3的结构清楚地表明，硫酯周围的主链在活化后会经历螺旋形转变。提出该重排是硫酯基团高反应性的基础。建议严格保守的谷氨酸残基在硫酯蛋白中起催化作用。 C3活化抑制剂的基于结构的设计可能靶向C3的α链和β链之间的保守口袋，这对于C3的构象变化而言似乎是必不可少的。

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