Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome
Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome
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DOI：
10.1182/blood-2014-10-609073
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发表时间：
2015-04-09
期刊：
影响因子：
20.3
通讯作者：
Fremeaux-Bacchi, Veronique
中科院分区：
文献类型：
--
作者：
Schramm, Elizabeth C.;Roumenina, Lubka T.;Fremeaux-Bacchi, Veronique
非典型溶血性尿毒症综合征(AHUS)的发病机制与补体系统替代途径的失调密切相关。在大约三分之二的病例中发现了补体基因的突变，其中5%到15%发生在C3。在这项研究中，23个与AHUS相关的C3基因改变与它们与控制蛋白因子H(FH)、膜辅助因子蛋白(MCP；CD46)和补体受体1(CR1；CD35)的相互作用有关。在表面等离子体共振实验中，17个突变型重组蛋白与FH和/或MCP结合缺陷，2个突变重组蛋白与CR1结合减少。在大多数情况下，结合亲和力降低会通过FH和MCP降低C3b的蛋白水解性失活(称为辅因子活性)。这些结果被用来定位C3b与MCP和CR1相互作用的推测结合区，并相对于已知的FH结合位点进行查询。76%的C3突变患者的C3水平较低，这与疾病严重程度有关。这项研究扩大了我们对aHUS相关C3突变的功能后果的了解，这些突变与C3与介导辅因子活性的补体调节蛋白相互作用有关。
The pathogenesis of atypical hemolytic uremic syndrome (aHUS) is strongly linked to dysregulation of the alternative pathway of the complement system. Mutations in complement genes have been identified in about two-thirds of cases, with 5% to 15% being in C3. In this study, 23 aHUS-associated genetic changes in C3 were characterized relative to their interaction with the control proteins factor H (FH), membrane cofactor protein (MCP; CD46), and complement receptor 1 (CR1; CD35). In surface plasmon resonance experiments, 17 mutant recombinant proteins demonstrated a defect in binding to FH and/or MCP, whereas 2 demonstrated reduced binding to CR1. In the majority of cases, decreased binding affinity translated to a decrease in proteolytic inactivation (known as cofactor activity) of C3b via FH and MCP. These results were used to map the putative binding regions of C3b involved in the interaction with MCP and CR1 and interrogated relative to known FH binding sites. Seventy-six percent of patients with C3 mutations had low C3 levels that correlated with disease severity. This study expands our knowledge of the functional consequences of aHUS-associated C3 mutations relative to the interaction of C3 with complement regulatory proteins mediating cofactor activity.