Classifying the Binding Modes of Disordered Proteins.

Monika Fuxreiter,Monika Fuxreiter

doi:10.3390/ijms21228615

Abstract

Disordered proteins often act as interaction hubs in cellular pathways, via the specific recognition of a distinguished set of partners. While disordered regions can adopt a well-defined conformation upon binding, the coupled folding to binding model does not explain how interaction versatility is achieved. Here, I present a classification scheme for the binding modes of disordered protein regions, based on their conformational heterogeneity in the bound state. Binding modes are defined as (i) disorder-to-order transitions leading to a well-defined bound state, (ii) disordered binding leading to a disordered bound state and (iii) fuzzy binding when the degree of disorder in the bound state may vary with the partner or cellular conditions. Fuzzy binding includes polymorphic bound structures, conditional folding and dynamic binding. This classification scheme describes the structural continuum of complexes involving disordered regions as well as their context-dependent interaction behaviors.

Highlights

Interactions mediated by disordered protein regions are critical for the regulation of numerous cellular pathways [1,2]
Extensive fluctuations of the well-defined secondary structure elements in the bound state of disordered proteins underscore the complexity of the templated folding pathway [11]
The bound state of disordered regions can vary along a continuum between order and disorder

Summary

Introduction

Interactions mediated by disordered protein regions are critical for the regulation of numerous cellular pathways [1,2]. Preformed secondary structures are frequently observed in complexes involving disordered regions [7], increasing experimental evidence underscores the plasticity of the templated folding pathway [8]. Extensive fluctuations of the well-defined secondary structure elements in the bound state of disordered proteins underscore the complexity of the templated folding pathway [11]. The fine-tuned equilibrium between ordered and disordered states in the complexes of disordered proteins often contributes to their regulatory roles. All these observations prompt a model that can describe the large variety and plasticity of bound conformations, along with their sensitivity to the cellular environment. This approach is based on a biophysical framework related to conformational entropy, which can be applied to predict binding modes from sequence

The Framework for Defining Binding Modes

Disorder-to-Order Transition

Disordered Binding

Fuzzy Binding

Sequence Codes for Binding Modes of Disordered Proteins