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Review
. 2020 May 8;295(19):6586-6593.
doi: 10.1074/jbc.REV120.012413. Epub 2020 Apr 6.

Templated folding of intrinsically disordered proteins

Angelo Toto  1 , Francesca Malagrinò  1 , Lorenzo Visconti  1 , Francesca Troilo  1 , Livia Pagano  1 , Maurizio Brunori  1 , Per Jemth  2 , Stefano Gianni  3
Affiliations
Review

Templated folding of intrinsically disordered proteins

Angelo Toto et al. J Biol Chem. .

Abstract

Much of our current knowledge of biological chemistry is founded in the structure-function relationship, whereby sequence determines structure that determines function. Thus, the discovery that a large fraction of the proteome is intrinsically disordered, while being functional, has revolutionized our understanding of proteins and raised new and interesting questions. Many intrinsically disordered proteins (IDPs) have been determined to undergo a disorder-to-order transition when recognizing their physiological partners, suggesting that their mechanisms of folding are intrinsically different from those observed in globular proteins. However, IDPs also follow some of the classic paradigms established for globular proteins, pointing to important similarities in their behavior. In this review, we compare and contrast the folding mechanisms of globular proteins with the emerging features of binding-induced folding of intrinsically disordered proteins. Specifically, whereas disorder-to-order transitions of intrinsically disordered proteins appear to follow rules of globular protein folding, such as the cooperative nature of the reaction, their folding pathways are remarkably more malleable, due to the heterogeneous nature of their folding nuclei, as probed by analysis of linear free-energy relationship plots. These insights have led to a new model for the disorder-to-order transition in IDPs termed "templated folding," whereby the binding partner dictates distinct structural transitions en route to product, while ensuring a cooperative folding.

Keywords: folding kinetics; intrinsically disordered protein; mutagenesis; protein chemistry; protein denaturation; protein folding; reaction mechanism; transition state.

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Conflict of interest statement

The authors declare that they have no conflicts of interest with the contents of this article

Figures

Figure 1.
Figure 1.
Induced folding of intrinsically disordered proteins. It is well-known that some IDPs undergo a disorder-to-order transition upon binding their physiological partner. Nevertheless, the level of disorder retained in the complex may vary substantially in different cases. The figure reports two cases: the complex between KIX and pKID (23) and that between GCN4 and Med15 (90).
Figure 2.
Figure 2.
LFER analysis of the IDP c-Myb binding to KIX. Thermodynamic parameters were measured for the binding reaction between the intrinsically disordered protein c-Myb and the globular domain KIX, either the WT or three site-directed variants (I26V, L43A, I72V). The structural ensemble of the transition state of c-Myb (in gray) and its average structure (in blue) for the binding reaction with the different variants of KIX are shown below the respective LFER plot (data taken from Ref. 67). In each plot, each point represents to the change in activation free energy versus that of the bound state measured for a single site-directed mutant.
Figure 3.
Figure 3.
Homogeneous and heterogeneous nucleation in protein folding. Folding pathways of globular proteins (top) are characterized by a robust transition state, which forms through a homogeneous nucleation process. On the other hand, folding of IDPs may take place via heterogeneous nucleation and, therefore, may display a remarkable malleability of the transition state. The latter scenario is characteristic of the so-called “template folding” mechanism.
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