On the Origins of Intrinsically Disordered Proteins

Abstract

A large number of proteins are sufficiently unstable that their full three dimensional 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 novel 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 using the Gene Ontology classification, in which Protein Binding, Catalytic Activity and Transcription Regulator Activity are the three largest functional categories, and 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 (Kd > 10−7 M) proteins prefer ordered structures, while 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.