The spatial architecture of protein function and adaptation.
The spatial architecture of protein function and adaptation.
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DOI：
10.1038/nature11500
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发表时间：
2012-11-01
期刊：
影响因子：
64.8
通讯作者：
Ranganathan, Rama
中科院分区：
文献类型：
--
作者：
McLaughlin, Richard N., Jr.;Poelwijk, Frank J.;Raman, Arjun;Gosal, Walraj S.;Ranganathan, Rama
蛋白质进化的统计分析提出了一种天然蛋白质的设计，其中共同进化的氨基酸（称为扇区）的稀疏网络构成了三维结构和功能的本质。然而，蛋白质也受到来自进化过程本身动力学的压力——容忍突变和适应不断变化的选择压力的能力。为了了解扇区结构与这些特性的关系，我们开发了一种高通量定量方法，用于全面的单突变研究，其中每个位置都被每个其他氨基酸单独取代。利用PDZ结构域（PSD95pdz3）模型系统，我们发现扇区位置对突变的功能敏感，而非扇区位置对替代的容忍度更高。此外，我们发现对新的结合特异性的适应完全通过扇形残基内的变异而开始。仅两个位于配体结合位点附近和远离的扇形突变的组合就足以将PSD95pdz3的结合特异性定量地转换为一类切换配体。扇区内功能约束和适应性变异的定位对理解和工程蛋白质具有重要意义。
Statistical analysis of protein evolution suggests a design for natural proteins in which sparse networks of coevolving amino acids (termed sectors) comprise the essence of three-dimensional structure and function. However, proteins are also subject to pressures deriving from the dynamics of the evolutionary process itself—the ability to tolerate mutation and to be adaptive to changing selection pressures. To understand the relationship of the sector architecture to these properties, we developed a high-throughput quantitative method for a comprehensive single-mutation study in which every position is substituted individually to every other amino acid. Using a PDZ domain (PSD95pdz3) model system, we show that sector positions are functionally sensitive to mutation, whereas non-sector positions are more tolerant to substitution. In addition, we find that adaptation to a new binding specificity initiates exclusively through variation within sector residues. A combination of just two sector mutations located near and away from the ligand-binding site suffices to switch the binding specificity of PSD95pdz3 quantitatively towards a class-switching ligand. The localization of functional constraint and adaptive variation within the sector has important implications for understanding and engineering proteins.
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