Crystal structure of the catalytic domain of human complement C1s: a serine protease with a handle
Crystal structure of the catalytic domain of human complement C1s: a serine protease with a handle
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DOI：
10.1093/emboj/19.8.1755
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发表时间：
2000-04-17
期刊：
影响因子：
11.4
通讯作者：
Fontecilla-Camps, JC
中科院分区：
文献类型：
--
作者：
Gaboriaud, C;Rossi, V;Fontecilla-Camps, JC
C1是一种高度特异性的模块化丝氨酸蛋白酶，可介导C1复合物的蛋白水解活性，从而触发补体级联的激活。由第二补体控制蛋白（CCP2）模块和chymotrypsin样丝氨酸蛋白酶（SP）结构域组成的人C1s催化片段的晶体结构已经被确定并细化到1.7埃的分辨率。在活性位点周围的区域，SP结构显示出对附属底物结合位点的限制，这可能是导致C1s特异性较窄的原因。椭球形CCP2模块垂直于SP畴表面。这种排列是通过一个刚性的模块-结构域界面来维持的，该界面涉及缠绕在一起的富含脯氨酸和酪氨酸的多肽片段。SP和CCP2的相对取向与后者为C4底物提供额外的底物识别位点的事实是一致的。这种结构提供了在多种细胞外蛋白中保守的CCP-SP组装的第一个例子。讨论了其在C1活化机制中的意义。
C1s is the highly specific modular serine protease that mediates the proteolytic activity of the C1 complex and thereby triggers activation of the complement cascade. The crystal structure of a catalytic fragment from human C1s comprising the second complement control protein (CCP2) module and the chymotrypsinlike serine protease (SP) domain has been determined and refined to 1.7 Angstrom resolution. In the areas surrounding the active site, the SP structure reveals a restricted access to subsidiary substrate binding sites that could be responsible for the narrow specificity of C1s. The ellipsoidal CCP2 module is oriented perpendicularly to the surface of the SP domain. This arrangement is maintained through a rigid module-domain interface involving intertwined proline- and tyrosine-rich polypeptide segments. The relative orientation of SP and CCP2 is consistent with the fact that the latter provides additional substrate recognition sites for the C4 substrate. This structure provides a first example of a CCP-SP assembly that is conserved in diverse extracellular proteins. Its implications in the activation mechanism of C1 are discussed.