Abstract

In recent years, protein science has been revolutionized by the discovery of intrinsically disordered proteins (IDPs). In contrast to the classical paradigm that a given protein sequence corresponds to a defined structure and an associated function, we now know that proteins can be functional in the absence of a stable three-dimensional structure. In many cases, disordered proteins or protein regions become structured, at least locally, upon interacting with their physiological partners. Many, sometimes conflicting, hypotheses have been put forward regarding the interaction mechanisms of IDPs and the potential advantages of disorder for protein-protein interactions. Whether disorder may increase, as proposed, e.g., in the “fly-casting” hypothesis, or decrease binding rates, increase or decrease binding specificity, or what role pre-formed structure might play in interactions involving IDPs (conformational selection vs. induced fit), are subjects of intense debate. Experimentally, these questions remain difficult to address. Here, we review experimental studies of binding mechanisms of IDPs using NMR spectroscopy and transient kinetic techniques, as well as the underlying theoretical concepts and numerical methods that can be applied to describe these interactions at the atomic level. The available literature suggests that the kinetic and thermodynamic parameters characterizing interactions involving IDPs can vary widely and that there may be no single common mechanism that can explain the different binding modes observed experimentally. Rather, disordered proteins appear to make combined use of features such as pre-formed structure and flexibility, depending on the individual system and the functional context.

Highlights

  • The discovery of intrinsically disordered proteins (IDPs) has considerably enhanced our view of protein structure and function

  • Given the apparent frequency with which disorder occurs in the aforementioned functional contexts, questions arise as to how IDPs interact with their partners in the absence of well-structured binding sites, which mechanisms they employ to assure specific binding, and in general the advantages intrinsic disorder may have for protein-protein interactions

  • In another study relevant to the subject, we have investigated the interaction between disordered NTAIL and the PX domain of the phosphoprotein from Sendai virus (SeV) using relaxation dispersion nuclear magnetic resonance (NMR) experiments

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Summary

INTRODUCTION

The discovery of intrinsically disordered proteins (IDPs) has considerably enhanced our view of protein structure and function. Single-molecule experiments such as fluorescence resonance energy transfer (Gambin et al, 2011) or nanopore translocation (Japrung et al, 2013) have recently gained importance in studying binding reactions In parallel to these experimental techniques, modeling and computer simulations have increasingly contributed to our understanding of protein interactions at the atomic level, notably due to the development of various enhanced sampling techniques (Zhou and Bates, 2013; De Vivo et al, 2016). We have chosen to review recent progress in the field based on NMR spectroscopy and transient kinetics experiments, as well as molecular simulations

METHODOLOGY
A Synthetic View of IDP Folding and Binding
Findings
CONCLUDING REMARKS
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