Evolving new protein-protein interaction specificity through promiscuous intermediates.
Evolving new protein-protein interaction specificity through promiscuous intermediates.
复制标题
通过混杂中间体发展出新的蛋白质 - 蛋白质相互作用特异性。
DOI：
10.1016/j.cell.2015.09.055
复制
发表时间：
2015-10-22
期刊：
影响因子：
64.5
通讯作者：
Laub MT
中科院分区：
文献类型：
--
作者：
Aakre CD;Herrou J;Phung TN;Perchuk BS;Crosson S;Laub MT
相互作用的蛋白质通常共同进化，并且共同进化氨基酸的鉴定可以查明相互作用特异性所需的残基。这种方法通常假设一种蛋白质中的界面破坏性突变会在进化过程中驱动其伴侣中补偿性突变的选择。然而，该模型在补偿性变化之前需要一个非功能性的中间状态。或者，一种蛋白质的突变可以首先扩大其特异性，允许其伴侣发生变化，然后进行特异性限制性突变。使用细菌毒素-抗毒素系统，我们证明了第二种基于混交的模型的合理性。通过筛选大型界面突变体库，我们发现具有高特异性的毒素和抗毒素经常在序列空间中与更混杂的变体连接，这些变体可以在相互作用特异性的重编程过程中充当中间体。我们认为，大量的混杂变异促进了毒素-抗毒素系统和其他旁系同源蛋白质家族在进化过程中的扩展和多样化。
Interacting proteins typically coevolve, and the identification of coevolving amino acids can pinpoint residues required for interaction specificity. This approach often assumes that an interface-disrupting mutation in one protein drives selection of a compensatory mutation in its partner during evolution. However, this model requires a non-functional intermediate state prior to the compensatory change. Alternatively, a mutation in one protein could first broaden its specificity, allowing changes in its partner, followed by a specificity-restricting mutation. Using bacterial toxin-antitoxin systems, we demonstrate the plausibility of this second, promiscuity-based model. By screening large libraries of interface mutants, we show that toxins and antitoxins with high specificity are frequently connected in sequence space to more promiscuous variants that can serve as intermediates during a reprogramming of interaction specificity. We propose that the abundance of promiscuous variants promotes the expansion and diversification of toxin-antitoxin systems and other paralogous protein families during evolution.