Mouse complement regulatory protein Crry/p65 uses the specific mechanisms of both human decay-accelerating factor and membrane cofactor protein.
Mouse complement regulatory protein Crry/p65 uses the specific mechanisms of both human decay-accelerating factor and membrane cofactor protein.
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DOI：
10.1084/jem.181.1.151
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发表时间：
1995-01-01
期刊：
影响因子：
--
通讯作者：
Holers VM
中科院分区：
文献类型：
--
作者：
Kim YU;Kinoshita T;Molina H;Hourcade D;Seya T;Wagner LM;Holers VM
正常宿主细胞通过细胞表面补体调节蛋白而免受补体的破坏作用。在人类中，衰变加速因子（decay-accelerating factor，简称ERF）和膜辅因子蛋白（membrane cofactor protein，简称MCP）通过抑制C3和C5转化酶发挥生物学作用。MCP和MCP分别通过指定的衰变加速活性和因子I辅因子活性的特定机制来完成这一任务。在其他物种中，包括小鼠，这些蛋白质的结构和/或功能同源物尚未得到很好的表征。先前的研究表明，小鼠蛋白Crry/p65具有一定的自我保护补体调节蛋白的特性。例如，Crry/p65在多种鼠细胞上表达，并且当在人K562红白血病细胞上表达时，其在经典或替代补体途径的活化期间防止小鼠C3片段在细胞表面上的沉积。我们现在已经研究了因子I辅因子和Crry/p65的衰变加速活性。重组Crry/p65证明了因子I介导的小鼠C3 b和C4 b切割的辅因子活性。令人惊讶的是，Crry/p65还对经典途径C3转化酶表现出强烈的衰变加速活性，而对旁路途径C3转化酶表现出微弱的衰变加速活性。因此，小鼠Crry/p65使用人MCP和MCP两者的特定机制。虽然Crry/p65与MCP和CRP 10一样，含有C3/C4结合蛋白的串联短共有重复序列（SCR）特征，但Crry/p65不被认为是MCP或CRP 10的遗传同源物。因此，Crry/p65是一个物种中单个独特蛋白质中两种特异性活性进化保守的例子，这些活性分散到另一个物种中的单个蛋白质中。我们提出，在这个家庭中的重复SCR基序允许这种不寻常的进化过程发生，可能是由人类病原体如麻疹病毒使用MCP和CRYPIA受体驱动的。
Normal host cells are protected from the destructive action of complement by cell surface complement regulatory proteins. In humans, decay-accelerating factor (DAF) and membrane cofactor protein (MCP) play such a biologic role by inhibiting C3 and C5 convertases. DAF and MCP accomplish this task by specific mechanisms designated decay- accelerating activity and factor I cofactor activity, respectively. In other species, including mice, structural and/or functional homologues of these proteins are not yet well characterized. Previous studies have shown that the mouse protein Crry/p65 has certain characteristics of self-protecting complement regulatory proteins. For example, Crry/p65 is expressed on a wide variety of murine cells, and when expressed on human K562 erythroleukemic cells, it prevents deposition of mouse C3 fragments on the cell surface during activation of either the classical or alternative complement pathway. We have now studied factor I cofactor and decay-accelerating activities of Crry/p65. Recombinant Crry/p65 demonstrates cofactor activity for factor I-mediated cleavage of both mouse C3b and C4b. Surprisingly, Crry/p65 also exhibits decay- accelerating activity for the classical pathway C3 convertase strongly and for the alternative pathway C3 convertase weakly. Therefore, mouse Crry/p65 uses the specific mechanisms of both human MCP and DAF. Although Crry/p65, like MCP and DAF, contains tandem short consensus repeats (SCR) characteristic of C3/C4 binding proteins, Crry/p65 is not considered to be a genetic homologue of either MCP or DAF. Thus, Crry/p65 is an example of evolutionary conservation of two specific activities in a single unique protein in one species that are dispersed to individual proteins in another. We propose that the repeating SCR motif in this family has allowed this unusual process of evolution to occur, perhaps driven by the use of MCP and DAF as receptors by human pathogens such as the measles virus.