Mini Review
Reconciling binding mechanisms of intrinsically disordered proteins

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Abstract

In recent years, intrinsically disordered proteins (IDPs) have attracted a lot of attention given the functional importance inherent to their flexible nature. One of the most intriguing features of IDPs is their ability to undergo disorder-to-order transitions upon binding in order to perform their function. Although the importance of intermolecular interactions involving IDPs has been widely recognized, there are divergent views on their binding mechanisms. Among the existing mechanistic models, two of them have gained popularity in the IDP field: the ‘conformational selection’ and the ‘coupled folding and binding.’ The first mechanism suggests that folding of IDPs precedes binding, while the second mechanism argues that folding may only take place upon binding. It has been suggested that both models are valid, although they work independently. However, reinterpretation of recent experimental and theoretical data indicates that both models have much more in common that it has been thought. In this manuscript, it is proposed that both mechanistic models should be merged into a single one: the synergistic model. In this model, both ‘conformational selection’ and ‘coupled folding and binding’ will synergistically participate in the binding of IDPs. To what extent each model will contribute to the full binding mechanism will depend on the required rate of binding, IDPs concentration, the native local plasticity of IDPs, the degree of binding degeneracy and the type of disorder-to-order transition. Furthermore, it is proposed that combination of the two mechanisms would bring tremendous advantages to IDP binding. For example, synergy may effectively modulate binding kinetics, balance the delicate interplay between enthalpy and entropy by using the funneled energy landscape more efficiently, thus yielding high specificity with carefully balanced free energy of binding. Given the advantages of the synergistic model, it is proposed that it will provide the basis to fully understand the complex nature of IDP binding.

Introduction

Until recently, the understanding of protein association has been rationalized on the basis of the ‘structure-function’ paradigm, where a well-defined three-dimensional arrangement is an indispensable requisite for binding. However, such dogma was recently challenged by the existence of intrinsically disordered proteins (IDPs) or natively unfolded proteins [1], [2], [3], [4], [5], [6]. Under physiological conditions, these proteins display a large degree of internal flexibility, ranging from coil-like structures, which are largely devoid of secondary and tertiary structure, to more ordered molten globule-like structures [3], [4], [7]. IDPs have garnered a lot of attention because of the functional importance inherent to their flexible nature. IDPs have often been found to regulate key cellular processes through binding to multiple targets [4], [8]; well documented examples of these IDPs are the tumor suppressor p53 [9], [10] and the transcription factor cAMP response-element binding protein (CREB) [11], [12].

One of the most intriguing features of IDPs is their ability to undergo disorder-to-order transitions upon binding in order to perform their function [13], [14], [15]. Binding of IDPs offers unique advantages in cellular signaling and regulation. For instance, the ability of IDPs to be molded by their binding partner ensures that binding to multiple targets will proceed selectively and with optimized binding rates. While there is a consensus opinion on the importance of intermolecular interactions involving IDPs, views on the possible mechanisms of binding are still divergent. Among the emerging mechanistic theories of IDP binding, two diametrically opposite models have been proposed: the ‘conformational selection’ and the ‘coupled folding and binding’. Both mechanistic models will be discussed in the following sections.

Section snippets

Conformational selection

This model was originally proposed as an extension of the theory of ‘folding funnel’, in which a protein explores the conformational landscape toward its low-energy (native) structure [16], [17], [18], [19]. In analogy to this concept, it has been proposed that folding and binding are mechanistically analogous, as both processes involve the location of molecular fragments in a funneled-like landscape, reducing the accessible configurational states (entropy) and consequently lowering the free

Coupled folding and binding

Unlike conformational selection, this disorder-to-order mechanism (also called ‘binding-induced folding’) proposes that folding of IDPs can only take place upon binding [13], [14]. Although in this hypothesis disorder-to-order transitions will be referred to as the gain of structural order upon binding (i.e., formation of defined secondary or tertiary structure), it is important to highlight that these transitions may occur in the absence of IDP folding [28], [29]. Similarly to the

Conformational selection and coupled folding and binding are synergistic

Mechanistically, both conformational selection and coupled folding and binding seem appealing to explain how IDPs bind to their partners. However, a key question arises: what model is ubiquitous in IDP binding?

To answer this question, it is necessary to consider that both models mechanistically rely on the theory of funneled energy landscapes. In this theory, folding is viewed as diffusion through an ensemble of conformational states characterized by reaction coordinates (i.e., the fraction of

Concluding remarks

Close analysis of the two most popular mechanisms of IDP binding not only suggests that they have more in common than what it has been thought, but also that they work synergistically. To what extent each model will contribute to the binding of IDPs will depend on different factors, such as rate of binding and local plasticity. Nonetheless, in the consensus synergistic model proposed here conformational selection will play the most important role in the specific encounter, while coupled folding

Acknowledgment

The author acknowledges the financial support from CONACYT.

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