Kim Y U, Kinoshita T, Molina H, Hourcade D, Seya T, Wagner L M, Holers V M
Department of Immunoregulation, Osaka University, Japan.
J Exp Med. 1995 Jan 1;181(1):151-9. doi: 10.1084/jem.181.1.151.
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.
正常宿主细胞通过细胞表面补体调节蛋白免受补体的破坏作用。在人类中，衰变加速因子（DAF）和膜辅因子蛋白（MCP）通过抑制C3和C5转化酶发挥这种生物学作用。DAF和MCP分别通过称为衰变加速活性和I因子辅因子活性的特定机制完成这项任务。在包括小鼠在内的其他物种中，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具有自我保护补体调节蛋白的某些特征。例如，Crry/p65在多种鼠细胞上表达，当在人K562红白血病细胞上表达时，它可防止在经典或替代补体途径激活期间小鼠C3片段沉积在细胞表面。我们现在研究了Crry/p65的I因子辅因子和衰变加速活性。重组Crry/p65对I因子介导的小鼠C3b和C4b裂解显示出辅因子活性。令人惊讶的是，Crry/p65对经典途径C3转化酶也具有很强的衰变加速活性，对替代途径C3转化酶具有较弱的衰变加速活性。因此，小鼠Crry/p65利用了人类MCP和DAF的特定机制。尽管Crry/p65与MCP和DAF一样，含有C3/C4结合蛋白特有的串联短共有重复序列（SCR），但Crry/p65不被认为是MCP或DAF的基因同源物。因此，Crry/p65是一个物种中单一独特蛋白质的两种特定活性在进化上保守的例子，而在另一个物种中这些活性分散到了不同的蛋白质中。我们提出，这个家族中的重复SCR基序使得这种不寻常的进化过程得以发生，这可能是由麻疹病毒等人类病原体将MCP和DAF用作受体所驱动的。
