Departments of Physics and Astronomy, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19819-23. doi: 10.1073/pnas.0907710106. Epub 2009 Nov 10.
A large number of proteins are sufficiently unstable that their full 3D structure cannot be resolved. The origins of this intrinsic disorder are not well understood, but its ubiquitous presence undercuts the principle that a protein's structure determines its function. Here we present a quantitative theory that makes predictions regarding the role of intrinsic disorder in protein structure and function. In particular, we discuss the implications of analytical solutions of a series of fundamental thermodynamic models of protein interactions in which disordered proteins are characterized by positive folding free energies. We validate our predictions by assigning protein function by using the gene ontology classification--in which "protein binding", "catalytic activity", and "transcription regulator activity" are the three largest functional categories--and by performing genome-wide surveys of both the amount of disorder in these functional classes and binding affinities for both prokaryotic and eukaryotic genomes. Specifically, without assuming any a priori structure-function relationship, the theory predicts that both catalytic and low-affinity binding (K(d) greater, >or= 0(-7) M) proteins prefer ordered structures, whereas only high-affinity binding proteins (found mostly in eukaryotes) can tolerate disorder. Relevant to both transcription and signal transduction, the theory also explains how increasing disorder can tune the binding affinity to maximize the specificity of promiscuous interactions. Collectively, these studies provide insight into how natural selection acts on folding stability to optimize protein function.
大量的蛋白质都不稳定，以至于无法确定其完整的 3D 结构。这种固有无序的起源尚不清楚，但它的普遍存在削弱了蛋白质结构决定其功能的原则。在这里，我们提出了一个定量理论，对内在无序在蛋白质结构和功能中的作用做出了预测。特别是，我们讨论了一系列蛋白质相互作用的基本热力学模型的分析解在其中无序蛋白质的特征是正折叠自由能的情况下所具有的意义。我们通过使用基因本体论分类（其中“蛋白质结合”、“催化活性”和“转录调节活性”是三个最大的功能类别）以及对这些功能类别中的无序程度和原核和真核基因组的结合亲和力进行全基因组调查，验证了我们的预测。具体而言，该理论无需假定任何先验的结构-功能关系，预测既具有催化活性又具有低亲和力结合（Kd 大于或等于 0(-7) M）的蛋白质偏爱有序结构，而只有高亲和力结合的蛋白质（主要存在于真核生物中）才能容忍无序。与转录和信号转导都相关，该理论还解释了增加无序度如何能够调节结合亲和力，以最大化混杂相互作用的特异性。总的来说，这些研究提供了关于自然选择如何作用于折叠稳定性以优化蛋白质功能的见解。
