Electrostatic contributions drive the interaction between Staphylococcus aureus protein Efb-C and its complement target C3d
Electrostatic contributions drive the interaction between Staphylococcus aureus protein Efb-C and its complement target C3d
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DOI：
10.1110/ps.036624.108
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发表时间：
2008-11-01
期刊：
影响因子：
8
通讯作者：
Lambris, John D.
中科院分区：
文献类型：
--
作者：
Haspel, Nurit;Ricklin, Daniel;Lambris, John D.
金黄色葡萄球菌胞外纤维蛋白原结合蛋白 (Efb-C) 的 C3 抑制结构域定义了一个调节补体激活的新型三螺旋束基序。先前对 Efb-C 与其人类 C3 (C3d) 的同源亚结构域结合的晶体学研究确定了 Efb-C 的 Arg-131 和 Asn-138 为其活性的关键残基。为了更全面地表征这种重要相互作用背后的物理和化学驱动力，我们在本研究中结合使用结构、生物物理和计算方法来分析 C3d 与 Efb-C 以及单点突变体 R131A 和 N138A 的相互作用。我们的结果表明，虽然这些突变不会显着影响 Efb-C/C3d 识别复合物的结构，但它们对所得复合物的热力学和动力学特征具有显着的不利影响。我们还表征了 Efb-C/C3d 结合界面上的其他关键相互作用，并发现了将 Efb-C 锚定到 C3d 的复杂的盐桥和氢键网络，从而产生了有效的补体抑制特性。
The C3-inhibitory domain of Staphylococcus aureus extracellular fibrinogen-binding protein (Efb-C) defines a novel three-helix bundle motif that regulates complement activation. Previous crystallographic studies of Efb-C bound to its cognate subdomain of human C3 (C3d) identified Arg-131 and Asn-138 of Efb-C as key residues for its activity. In order to characterize more completely the physical and chemical driving forces behind this important interaction, we employed in this study a combination of structural, biophysical, and computational methods to analyze the interaction of C3d with Efb-C and the single-point mutants R131A and N138A. Our results show that while these mutations do not drastically affect the structure of the Efb-C/C3d recognition complex, they have significant adverse effects on both the thermodynamic and kinetic profiles of the resulting complexes. We also characterized other key interactions along the Efb-C/C3d binding interface and found an intricate network of salt bridges and hydrogen bonds that anchor Efb-C to C3d, resulting in its potent complement inhibitory properties.