Intrinsic Disorder in Protein Interactions: Insights From a Comprehensive Structural Analysis

Jessica H Fong,Benjamin A Shoemaker,Anna R Panchenko,Michail Y Lobanov,Sergiy O Garbuzynskiy,Oxana V Galzitskaya,Keith Dunker

doi:10.1371/journal.pcbi.1000316

Abstract

We perform a large-scale study of intrinsically disordered regions in proteins and protein complexes using a non-redundant set of hundreds of different protein complexes. In accordance with the conventional view that folding and binding are coupled, in many of our cases the disorder-to-order transition occurs upon complex formation and can be localized to binding interfaces. Moreover, analysis of disorder in protein complexes depicts a significant fraction of intrinsically disordered regions, with up to one third of all residues being disordered. We find that the disorder in homodimers, especially in symmetrical homodimers, is significantly higher than in heterodimers and offer an explanation for this interesting phenomenon. We argue that the mechanisms of regulation of binding specificity through disordered regions in complexes can be as common as for unbound monomeric proteins. The fascinating diversity of roles of disordered regions in various biological processes and protein oligomeric forms shown in our study may be a subject of future endeavors in this area.

Highlights

Many proteins and protein regions have been shown to be intrinsically disordered under native conditions; namely, they contain no or very little well-defined structure [1,2,3,4,5,6]
Intrinsic disorder has been associated with particular functions including cell regulation; signaling; and protein, DNA, and ligand binding
We show that disorder in protein complexes is rather common and pinpoint changes that occur upon protein binding at interaction interfaces

Summary

Introduction

Many proteins and protein regions have been shown to be intrinsically disordered under native conditions; namely, they contain no or very little well-defined structure [1,2,3,4,5,6]. Disordered proteins (IDPs) have been found in a wide scope of organisms and their disorder content was shown to increase with organism complexity [7,8,9,10,11]. 2) Conformational changes upon binding in proteins with unstructured regions are much larger than those in structured proteins [1]. 3) The conformations of disordered regions in a protein complex are determined by the amino acid sequences and by the interacting partners [1,19]. Prediction methods aim to identify disordered regions through the analysis of amino acid sequences using mainly the physico-chemical properties of the amino acids [23,27,28,29,30,31,32,33,34,35,36] or evolutionary conservation [12,37,38,39]

Methods

Results

Discussion

Conclusion