Abstract：
Trypanosomes are known to activate the complement system on their surface, but they control the cascade in a manner such that the cascade does not progress into the terminal pathway. It was recently reported that the invariant surface glycoprotein ISG65 from Trypanosoma brucei interacts reversibly with complement C3 and its degradation products, but the molecular mechanism by which ISG65 interferes with complement activation remains unknown. In this study, we show that ISG65 does not interfere directly with the assembly or activity of the two C3 convertases. However, ISG65 acts as a potent inhibitor of C3 deposition through the alternative pathway in human and murine serum. Degradation assays demonstrate that ISG65 stimulates the C3b to iC3b converting activity of complement factor I in the presence of the cofactors factor H or complement receptor 1. A structure-based model suggests that ISG65 promotes a C3b conformation susceptible to degradation or directly bridges factor I and C3b without contact with the cofactor. In addition, ISG65 is observed to form a stable ternary complex with the ligand binding domain of complement receptor 3 and iC3b. Our data suggest that ISG65 supports trypanosome complement evasion by accelerating the conversion of C3b to iC3b through a unique mechanism.
摘要：
已知锥虫能激活其表面的补体系统,但它们控制级联的方式使得级联不进入末端途径。最近报道，来自布鲁氏锥虫的不变表面糖蛋白ISG65与补体C3及其降解产物可逆地相互作用，但ISG65干扰补体激活的分子机制尚不清楚.在这项研究中,我们显示ISG65不直接干扰两种C3转化酶的组装或活性。然而,ISG65在人和鼠血清中通过旁路途径作为C3沉积的有效抑制剂。降解测定表明,ISG65在辅因子因子H或补体受体1存在下刺激补体因子I的C3b至iC3b转化活性。基于结构的模型表明ISG65促进易于降解的C3b构象或直接桥接因子I和C3b而不与辅因子接触。此外,观察到ISG65与补体受体3的配体结合结构域和iC3b形成稳定的三元复合物。我们的数据表明，ISG65通过独特的机制加速C3b向iC3b的转化，从而支持锥虫补体逃避。
