Toward a quantitative theory of intrinsically disordered proteins and their function

被引:82
作者
Liu, Jintao [2 ]
Faeder, James R. [1 ]
Camacho, Carlos J. [1 ]
机构
[1] Univ Pittsburgh, Dept Computat Biol, Pittsburgh, PA 15260 USA
[2] Univ Pittsburgh, Dept Phys & Astron, Pittsburgh, PA 15260 USA
基金
美国国家科学基金会;
关键词
binding; catalysis; intrinsic disorder; specificity; transcription; GENE ONTOLOGY; UNSTRUCTURED PROTEINS; DATABASE; PREDICTION; SITE; TOOL;
D O I
10.1073/pnas.0907710106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 than or similar to 10(-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.
引用
收藏
页码:19819 / 19823
页数:5
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