Molecular Interactions between Complement Factor H and Its Heparin and Heparan Sulfate Ligands.
Molecular Interactions between Complement Factor H and Its Heparin and Heparan Sulfate Ligands.
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DOI：
10.3389/fimmu.2014.00126
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发表时间：
2014
影响因子：
7.3
通讯作者：
Khan S
中科院分区：
文献类型：
--
作者：
Perkins SJ;Fung KW;Khan S
补体因子H（CFH）是补体激活旁路途径中中心补体蛋白C3 b的主要调节因子。CFH与天然硫酸乙酰肝素（HS）相互作用的分子观点是理解表面结合的CFH如何与结合到宿主细胞表面的C3 b相互作用的机制的核心。HS由硫酸化肝素样S-区与硫酸化NA-区交替组成。通过散射和超离心对肝素（相当于S-区）和肝素化HS（NA-区）进行的溶液结构研究表明，每个结构大部分是延伸的，部分是弯曲的，但与S-区相比，NA-区的弯曲和柔韧性更大。它们的溶液结构已存入蛋白质数据库。最大的HS寡糖显示出更多的弯曲和灵活的结构比肝素。同样确定CFH中20个结构域的溶液结构的折回结构域结构。CFH与HS的S区结合，但与NA区结合较少。CFH-肝素的二价相互作用通过超离心和CFH片段与肝素涂层传感器芯片的结合研究来观察。与其他CFH与其生理和病理生理配体的相互作用一样，CFH-肝素和CFH-C3 b相互作用具有中等微摩尔解离常数KD，这意味着这些复合物在体内不完全形成。结合的解决方案的结构和结合的研究表明，在细胞表面的两个网站的相互作用模型的CFH与肝素。由此，CFH与细胞表面的二价结合是协同的。在两个独立的CFH-肝素位点中的任一个处的缺陷相互作用减少CFH与表面结合的C3 b的相互作用并导致免疫紊乱。
Complement factor H (CFH) is the major regulator of the central complement protein C3b in the alternative pathway of complement activation. A molecular view of the CFH interaction with native heparan sulfate (HS) is central for understanding the mechanism of how surface-bound CFH interacts with C3b bound to host cell surfaces. HS is composed of sulfated heparin-like S-regions that alternate with desulfated NA-regions. Solution structural studies of heparin (equivalent to the S-regions) and desulfated HS (the NA-regions) by scattering and ultracentrifugation showed that each structure was mostly extended and partially bent, but with greater bending and flexibility in the NA-regions compared to the S-regions. Their solution structures have been deposited in the Protein Data Bank. The largest HS oligosaccharides showed more bent and flexible structures than those for heparin. A folded-back domain structure for the solution structure of the 20 domains in CFH was determined likewise. CFH binds to the S-regions but less so to the NA-regions of HS. The bivalent interaction of CFH–heparin was observed by ultracentrifugation, and binding studies of CFH fragments with heparin-coated sensor chips. In common with other CFH interactions with its physiological and pathophysiological ligands, the CFH–heparin and CFH–C3b interactions have moderate micromolar dissociation constants KD, meaning that these complexes do not fully form in vivo. The combination of the solution structures and binding studies indicated a two-site interaction model of CFH with heparin at cell surfaces. By this, the bivalent binding of CFH to a cell surface is co-operative. Defective interactions at either of the two independent CFH–heparin sites reduce the CFH interaction with surface-bound C3b and lead to immune disorders.
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DOI：
10.1074/jbc.m113.476143
发表时间：
2013-06-28
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Nan R;Tetchner S;Rodriguez E;Pao PJ;Gor J;Lengyel I;Perkins SJ
通讯作者：
Perkins SJ
影响因子：
4.8
作者：
Khan, Sanaullah;Rodriguez, Elizabeth;Perkins, Stephen J.
通讯作者：
Perkins, Stephen J.
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
影响因子：
5.6
作者：
Nan, Ruodan;Gor, Jayesh;Perkins, Stephen J.
通讯作者：
Perkins, Stephen J.
影响因子：
5.6
作者：
Khan, Sanaullah;Gor, Jayesh;Perkins, Stephen J.
通讯作者：
Perkins, Stephen J.