Insights into complement convertase formation based on the structure of the factor B-cobra venom factor complex
Insights into complement convertase formation based on the structure of the factor B-cobra venom factor complex
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DOI：
10.1038/emboj.2009.184
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发表时间：
2009-08-19
期刊：
影响因子：
11.4
通讯作者：
Gros, Piet
中科院分区：
文献类型：
--
作者：
Janssen, Bert J. C.;Gomes, Lucio;Gros, Piet
补体系统的免疫保护关键取决于病原体和改变的宿主细胞表面上C3转化酶的组装。这些短寿命蛋白酶复合物通过前转化酶形成，其对于旁路途径由补体组分C3 B和前酶因子B（FB）组成。在这里，我们提出的晶体结构在2.2埃分辨率，小角度X射线散射和电子显微镜（EM）数据的前转化酶形成的人FB和眼镜蛇毒因子（CVF），一个有效的同系物C3 b，产生更稳定的转化酶。FB通过其前肽Ba片段通过特异性接触加载到CVF上，这解释了同源C3 b相对于天然C3和无活性产物iC 3b和C3 c的特异性。蛋白酶区段Bb通过血管性血友病因子A型结构域的金属离子依赖性粘附位点结合CVF的羧基末端。前转化酶的“负载”和“活化”状态之间可能的动态平衡可以解释CVFB的晶体结构和C3 bB的EM结构之间观察到的差异。这些对转化酶形成的见解为进一步开发补体治疗剂提供了基础。The EMBO Journal（2009）28，2469-2478. doi：10.1038/doj.2009.184; 2009年7月2日在线发布
Immune protection by the complement system critically depends on assembly of C3 convertases on the surface of pathogens and altered host cells. These short-lived protease complexes are formed through pro-convertases, which for the alternative pathway consist of the complement component C3b and the pro-enzyme factor B (FB). Here, we present the crystal structure at 2.2-angstrom resolution, small-angle X-ray scattering and electron microscopy (EM) data of the pro-convertase formed by human FB and cobra venom factor (CVF), a potent homologue of C3b that generates more stable convertases. FB is loaded onto CVF through its pro-peptide Ba segment by specific contacts, which explain the specificity for the homologous C3b over the native C3 and inactive products iC3b and C3c. The protease segment Bb binds the carboxy terminus of CVF through the metal-ion dependent adhesion site of the Von Willebrand factor A-type domain. A possible dynamic equilibrium between a 'loading' and 'activation' state of the pro-convertase may explain the observed difference between the crystal structure of CVFB and the EM structure of C3bB. These insights into formation of convertases provide a basis for further development of complement therapeutics. The EMBO Journal (2009) 28, 2469-2478. doi:10.1038/emboj.2009.184; Published online 2 July 2009