Backbone dynamics of complement control protein (CCP) modules reveals mobility in binding surfaces
Backbone dynamics of complement control protein (CCP) modules reveals mobility in binding surfaces
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DOI：
10.1110/ps.03582704
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发表时间：
2004-05-01
期刊：
影响因子：
8
通讯作者：
Barlow, PN
中科院分区：
文献类型：
--
作者：
O'Leary, JM;Bromek, K;Barlow, PN
补体激活（RCA）的调节因子对健康和疾病至关重要，因为它们的作用是确保补体介导的对感染的免疫应答是成比例的和有针对性的。每种蛋白质都包含一个不间断的阵列，其中包含4到30个非常广泛存在的补体控制蛋白（CCP或sushi）模块。CCP模块介导特异性蛋白质-蛋白质和蛋白质-碳水化合物相互作用，这是RCA生物学功能的关键，并且矛盾的是，为许多病原体提供结合位点。尽管CCP模块的结构和诱变研究已经解决了分子识别的某些方面，但还没有研究CCP模块与其结合伴侣相互作用中分子动力学的作用。NMR现在已被用于CCP模块的骨架动力学的第一个完整的表征。动态的两个单独的模块的30个模块的补体受体1型（CD 35）的第16，和膜辅因子蛋白（CD 46）的N-末端模块，以及它们的解决方案的结构，进行了比较。虽然这两个例子共享广泛相似的三维结构，许多结构上等同的残基表现出不同的幅度和局部骨架运动的时间尺度。然而，在每种情况下，作为与其他蛋白质相互作用位点的诱变所涉及的模块表面区域包括几个移动的残基。这一观察结果表明，进一步的实验，探索结合机制，并确定新的结合位点。
The regulators of complement activation (RCA) are critical to health and disease because their role is to ensure that a complement-mediated immune response to infection is proportionate and targeted. Each protein contains an uninterrupted array of from four to 30 examples of the very widely occurring complement control protein (CCP, or sushi) module. The CCP modules mediate specific protein-protein and protein-carbohydrate interactions that are key to the biological function of the RCA and, paradoxically, provide binding sites for numerous pathogens. Although structural and mutagenesis studies of CCP modules have addressed some aspects of molecular recognition, there have been no studies of the role of molecular dynamics in the interaction of CCP modules with their binding partners. NMR has now been used in the first full characterization of the backbone dynamics of CCP modules. The dynamics of two individual modules the 16th of the 30 modules of complement receptor type 1 (CD35), and the N-terminal module of membrane cofactor protein (CD46)-as well as their solution structures, are compared. Although both examples share broadly similar three-dimensional structures, many structurally equivalent residues exhibit different amplitudes and timescales of local backbone motion. In each case, however, regions of the module-surface implicated by mutagenesis as sites of interactions with other proteins include several mobile residues. This observation suggests further experiments to explore binding mechanisms and identify new binding sites.