The regulatory SCR-1/5 and cell surface-binding SCR-16/20 fragments of factor H reveal partially folded-back solution structures and different self-associative properties
The regulatory SCR-1/5 and cell surface-binding SCR-16/20 fragments of factor H reveal partially folded-back solution structures and different self-associative properties
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DOI：
10.1016/j.jmb.2007.09.026
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发表时间：
2008-01-04
影响因子：
5.6
通讯作者：
Perkins, Stephen J.
中科院分区：
文献类型：
--
作者：
Okemefuna, Azubuike I.;Gilbert, Hannah E.;Perkins, Stephen J.
因子H（FH）是一种血浆糖蛋白，在补体旁路途径的调节中发挥核心作用。它由20个短补体调节因子（SCR）结构域组成。SCR-1/5片段是衰变加速和辅因子活性所需的，而SCR-16/20片段具有补体C3 d和肝素的结合位点。X射线散射和分析超离心表明SCR-1/5是单体，而SCR-16/20形成二聚体。SCR-1/5的4.3 nm的Guinier回转半径R-G以及单体和二聚体SCR-16/20的分别为4.7 nm和约7.8 nm的Guinier回转半径R-G表明它们的结构是部分向后折叠和弯曲的。距离分布函数P（r）显示SCR-15具有15 nm的最大尺寸，而单体和二聚体SCR-16/20分别为17 nm和约27 nm长。SCR-1/5的沉降系数为2.4 S，显示无浓度依赖性，而SCR-16/20的单体沉降系数为2.8 S，二聚体沉降系数为3.9 S。沉降平衡数据表明，SCR-1/5是单体，而SCR-16/20表现出弱的单体-二聚体平衡，解离常数为16 μ M。SCR-1/5和SCR-16/20的约束散射和沉降建模表明，部分折回和弯曲的柔性SCR排列比扩展的线性排列更好地拟合这两个数据集，并且二聚体在SCR-16/20模型中通过两个SCR-20结构域的端对端关联来最好地建模。SCR-1/5和SCR-16/20模型在构象上与先前确定的完整野生型FH的部分折回结构相似，因此表明完整FH结构的部分解释。SCR-16/20模型与C3 b晶体结构的比较阐明了导致非典型溶血性尿毒综合征的突变分布的原因。(c)2007爱思唯尔有限公司版权所有。
Factor H (FH) is a plasma glycoprotein that plays a central role in regulation of the alternative pathway of complement. It is composed of 20 short complement regulator (SCR) domains. The SCR-1/5 fragment is required for decay acceleration and cofactor activity, while the SCR-16/20 fragment possesses binding sites for complement C3d and heparin. X-ray scattering and analytical ultracentrifugation showed that SCR-1/5 was monomeric, while SCR-16/20 formed dimers. The Guinier radius of gyration R-G of 4.3 nm for SCR-1/5 and those of 4.7 nm and about 7.8 nm for monomeric and dimeric SCR-16/20, respectively, showed that their structures are partially folded back and bent. The distance distribution function P(r) showed that SCR-1/5 has a maximum dimension of 15 nm while monomeric and dimeric SCR-16/20 are 17 nm and about 27 nm long, respectively. The sedimentation coefficient of 2.4 S for SCR-1/5 showed no concentration-dependence, while that for SCR-16/20 was 2.8 S for the monomer and 3.9 S for the dimer. Sedimentation equilibrium data showed that SCR-1/5 is monomeric while SCR-16/20 exhibited a weak monomer-dimer equilibrium with a dissociation constant of 16 mu M. The constrained scattering and sedimentation modelling of SCR-1/5 and SCR-16/20 showed that partially folded-back and bent flexible SCR arrangements fitted both data sets better than extended linear arrangements, and that the dimer was best modelled in the SCR-16/20 model by an end-to-end association of two SCR-20 domains. The SCR-1/5 and SCR-16/20 models were conformationally similar to the previously determined partially folded-back structure for intact wild-type FH, hence suggesting a partial explanation of the intact FH structure. Comparison of the SCR-16/20 model with the crystal structure of C3b clarified reasons for the distribution of mutations leading to atypical haemolytic uraemic syndrome. (c) 2007 Elsevier Ltd. All rights reserved.