The modular architecture of protein-protein binding interfaces
The modular architecture of protein-protein binding interfaces
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DOI：
10.1073/pnas.0407280102
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发表时间：
2005-01-04
影响因子：
11.1
通讯作者：
Schreiber, G
中科院分区：
文献类型：
--
作者：
Reichmann, D;Rahat, O;Schreiber, G
蛋白质之间的相互作用对生命至关重要。然而，我们对控制绑定的一般原则的理解并不完整。在目前的研究中，我们表明蛋白质之间的界面是以模块化的方式构建的；每个模由许多紧密相互作用的残基组成，模间相互作用很少。模块之间的边界是通过聚集接口的接触映射来定义的。我们证明了一个模的突变不会影响相邻模的残基。因此，删除整个模块的结构和能量后果非常小。相反，在它们的模块内，突变会导致复杂的能量和结构后果。实验中，利用多突变体分析和x射线晶体学研究了tem1 - β -内酰胺酶与β -内酰胺酶抑制剂蛋白（BLIP）的相互作用。用Ala代替整个模块的五个界面残留物，在界面中产生了一个大的空腔，对剩余界面的详细结构没有影响。结合位点的模块化结构，类似于人类工程设计，极大地简化了新的蛋白质相互作用的设计，并提供了这些相互作用如何进化的可行观点。
Protein-protein interactions are essential for life. Yet, our understanding of the general principles governing binding is not complete. In the present study, we show that the interface between proteins is built in a modular fashion; each module is comprised of a number of closely interacting residues, with few interactions between the modules. The boundaries between modules are defined by clustering the contact map of the interface. We show that mutations in one module do not affect residues located in a neighboring module. As a result, the structural and energetic consequences of the deletion of entire modules are surprisingly small. To the contrary, within their module, mutations cause complex energetic and structural consequences. Experimentally, this phenomenon is shown on the interaction between TEM1-beta-lactamase and beta-lactamase inhibitor protein (BLIP) by using multiple-mutant analysis and x-ray crystallography. Replacing an entire module of five interface residues with Ala created a large cavity in the interface, with no effect on the detailed structure of the remaining interface. The modular architecture of binding sites, which resembles human engineering design, greatly simplifies the design of new protein interactions and provides a feasible view of how these interactions evolved.