Department of Molecular Biology & Genetics, Johns Hopkins University School of Medicine, Room 507 PCTB, 725 North Wolfe Street, Baltimore, MD 21205, USA.
Department of Molecular Biology & Genetics, Johns Hopkins University School of Medicine, Room 507 PCTB, 725 North Wolfe Street, Baltimore, MD 21205, USA.
Structure. 2020 Dec 1;28(12):1329-1336.e4. doi: 10.1016/j.str.2020.07.015. Epub 2020 Aug 13.
How evolution endowed membrane enzymes with specific abilities, and then tuned them to the needs of different cells, is poorly understood. We examined whether statistical coupling analysis (SCA) can be applied to rhomboid proteases, the most widely distributed membrane proteins, to identify amino acid "sectors" that evolved independently to acquire a specific function. SCA revealed three coevolving residue networks that form two sectors. Sector 1 determines substrate specificity, but is paradoxically scattered across the protein, consistent with dynamics driving rhomboid-substrate interactions. Sector 2 is hierarchically composed of a subgroup that maintains the catalytic site, and another that maintains the overall fold, forecasting evolution of rhomboid pseudoproteases. Changing only sector 1 residues of a "recipient" rhomboid converted its substrate specificity and catalytic efficiency to that of the "donor." While used only twice over a decade ago, SCA should be generally applicable to membrane proteins, and our sector grafting approach provides an efficient strategy for designing enzymes.
进化是如何赋予膜酶特定的能力，然后根据不同细胞的需求对其进行调整，目前还知之甚少。我们研究了统计耦合分析（SCA）是否可以应用于广泛分布的膜蛋白——类蛋白水解酶，以识别出独立进化以获得特定功能的氨基酸“区域”。SCA 揭示了形成两个区域的三个共同进化的残基网络。第 1 区域决定了底物特异性，但却矛盾地分散在整个蛋白质中，这与驱动类蛋白水解酶-底物相互作用的动力学一致。第 2 区由一个维持催化位点的子组和另一个维持整体折叠的子组组成，预测了类蛋白假酶的进化。仅改变“受体”类蛋白水解酶的第 1 区域残基，就可以将其底物特异性和催化效率转换为“供体”的。虽然 SCA 仅在十年前使用过两次，但它应该普遍适用于膜蛋白，并且我们的区域嫁接方法为设计酶提供了一种有效的策略。
