The disease-protective complement factor H allotypic variant Ile62 shows increased binding affinity for C3b and enhanced cofactor activity.
The disease-protective complement factor H allotypic variant Ile62 shows increased binding affinity for C3b and enhanced cofactor activity.
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DOI：
10.1093/hmg/ddp289
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发表时间：
2009-09-15
影响因子：
3.5
通讯作者：
de Córdoba SR
中科院分区：
文献类型：
--
作者：
Tortajada A;Montes T;Martínez-Barricarte R;Morgan BP;Harris CL;de Córdoba SR
基因编码因子H（CFH）的突变和多态性与非典型溶血性尿毒症综合征、致密存款病和年龄相关性黄斑变性有关。疾病易感性CFH变体显示出与病理学的差异相关性，这对于揭示一种或其他疾病发病机制中的关键事件非常有用。相比之下，fH-Ile 62多态性对所有三种疾病都有很强的保护作用。使用基于ELISA的方法和表面等离子体共振分析，我们在这里表明，保护性fH-Ile 62变体比fH-Val 62更有效地与C3 B结合，并且在前转化酶形成中与因子B更好地竞争。功能分析表明，增加的辅因子活性fH-Ile 62在因子I介导的裂解的流体相和表面结合的C3 b，然而，两个fH的变体显示衰变加速活性没有差异。从这些数据中，我们得出结论，fH-Ile 62变体的保护作用是由于其更好的结合C3 b、抑制前转化酶形成和催化液相和表面结合的C3 b失活的能力。fH-Ile 62多态性的功能后果的证明提供了对fH的补体调节活性的相关见解，这将有助于疾病预测和未来开发用于补体失调引起的疾病的有效疗法。
Mutations and polymorphisms in the gene encoding factor H (CFH) have been associated with atypical haemolytic uraemic syndrome, dense deposit disease and age-related macular degeneration. The disease-predisposing CFH variants show a differential association with pathology that has been very useful to unravel critical events in the pathogenesis of one or other disease. In contrast, the fH-Ile62 polymorphism confers strong protection to all three diseases. Using ELISA-based methods and surface plasmon resonance analyses we show here that the protective fH-Ile62 variant binds more efficiently to C3b than fH-Val62 and competes better with factor B in proconvertase formation. Functional analyses demonstrate an increased cofactor activity for fH-Ile62 in the factor I-mediated cleavage of fluid phase and surface-bound C3b; however, the two fH variants show no differences in decay accelerating activity. From these data we conclude that the protective effect of the fH-Ile62 variant is due to its better capacity to bind C3b, inhibit proconvertase formation and catalyse inactivation of fluid-phase and surface-bound C3b. This demonstration of the functional consequences of the fH-Ile62 polymorphism provides relevant insights into the complement regulatory activities of fH that will be useful in disease prediction and future development of effective therapeutics for disorders caused by complement dysregulation.
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DOI：
10.1073/pnas.0501536102
发表时间：
2005-05-17
影响因子：
11.1
作者：
Hageman, GS;Anderson, DH;Allikmets, R
通讯作者：
Allikmets, R
DOI：
10.1073/pnas.0812584106
发表时间：
2009-03-17
影响因子：
11.1
作者：
Montes, Tamara;Tortajada, Agustin;Harris, Claire L.
通讯作者：
Harris, Claire L.
影响因子：
3.6
作者：
Montes, Tamara;Goicoechea de Jorge, Elena;Rodriguez de Cordoba, Santiago
通讯作者：
Rodriguez de Cordoba, Santiago
影响因子：
4.8
作者：
Hepburn, Natalie J.;Williams, Anwen S.;Harris, Claire L.
通讯作者：
Harris, Claire L.
影响因子：
56.9
作者：
Edwards, AO;Ritter, R;Farrer, LA
通讯作者：
Farrer, LA