Review
Intrinsically disordered proteins: a 10-year recap

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The suggestion that the native state of many proteins is intrinsically disordered (or, as originally termed, unstructured) is now integral to our general view of protein structure and function. A little more than 10 years ago, however, such challenge to the almost dogmatic ‘structure–function paradigm’ was pure heresy due to the overwhelming evidence that structure determines function. A decade of steady progress turned skepticism around: this 10-year recap review outlines the situation a decade ago and the major directions of the breathtaking advance achieved by experimental and computational approaches. I show that the evidence for the generality and importance of this phenomenon is now so insurmountable that it demands the inclusion of ‘unstructural’ biology into mainstream biology and biochemistry textbooks.

Section snippets

Structural disorder taking over

Over the past century evidence steadily accumulated that a well-defined structure is the prerequisite of protein function. Basic biology and biochemistry textbooks that explain biological phenomena at the molecular level exquisitely rely on this notion, the ‘structure–function paradigm’. Although deviations from this norm were always apparent, they had been invariably neglected or ignored. Only around the turn of the millennium was it eventually formally raised in several conceptual papers 1, 2

Expanding evidence for disorder

As suggested [4], the transition in paradigm was enforced by scattered experimental observations of disorder in a few dozen proteins 1, 2, 3, whereas structural biology was at that time based on the ∼18 000 structures deposited in the Protein Data Bank (PDB) (which has now grown to more than 80 000 [10]). Intriguingly, thousands of the structures in PDB are now known to contain disordered chains that become structured only in the presence of the partner, and there are also many regions that are

IDPs are not unstructured but … pliable?

Although the initial name ‘unstructured’ implied that IDPs might completely lack structure, it was apparent even 10 years ago [4] that they have potentially function-related short- and long-range structural organization, which eventually called upon a change in terminology. At that time, high-resolution data were rather limited, thus the concept was mostly phrased from the global structural level, which suggested that IDPs fall into coil-like, pre-molten globule-type and molten-globule types

Disorder exists in vivo

A decade ago, a major unsolved mystery of the disorder field was whether structural disorder exists in vivo, or if it is an in vitro artifact caused by isolation and high dilution of the protein in the test tube. If this were the case, crowding elicited by extreme macromolecular concentrations and/or folding induced by physiological binding partners would actually make them fold in vivo.

Since then, several studies have suggested that these factors do not force IDPs to fold (fully) in the cell.

Functional modes of disordered proteins

The most important question of the field, therefore, is the physiological function and functional mode of IDPs/IDRs. As a result of breathtaking advances in comparative evolutionary and experimental structure–function studies, it is now clear that structural disorder provides multiple functional advantages, and IDP functions either directly stem from their disorder (entropic chains) or from molecular recognition, when they undergo induced folding (disorder-to-order transition) upon binding to a

Function of disordered proteins

The functional role of structural disorder from a biological process view addresses what type of cellular functions benefit most from the lack of a stable structure. This question was addressed in several large bioinformatics studies. As a result, IDPs are generally thought to be involved in processes of signaling and regulation, and in-depth correlation analysis [52] of 710 Swiss-Prot functional keywords suggested significant positive correlation with 238 functions and negative correlation

Structural disorder in disease

Ten years ago, we surmised that structural disorder might be involved in diseases [4], primarily because of its enrichment in a few important cases, such α-synuclein [64]. Structural disorder was then confirmed and/or studied in great detail in many other important disease-associated proteins, such as p53 [25], τ protein [23], and cystic fibrosis transmembrane conductance regulator (CFTR) [65], and was also substantiated by several genome-scale bioinformatics studies. In these, a significant

IDPs in drug development

Thus, the involvement of IDPs in disease makes them prime targets for drug development, which was not entirely apparent a decade ago. Of course, IDPs have no enzymatic activity and thus cannot be attacked in the way traditional drugs function, which usually target active sites or the ligand-binding pockets of enzymes and/or receptors [75]. However, as suggested above, they are often engaged in protein–protein interactions, which might be interfered with via small molecules. The interfaces of

Concluding remarks

The field of structural disorder has been – and still is – developing at a rapid pace. Intriguingly, many of the basic concepts such as its prevalence, functional associations, and functional advantages were correctly foreseen, yet the pace of discovery surpassed all expectations. The most notable new developments are: (i) the adaptation of structural techniques to the detailed description of their structural ensemble in vitro and in vivo; (ii) the advanced state of structural–functional

Acknowledgements

This work was supported by the Odysseus grant G.0029.12 from the Research Foundation Flanders (FWO). The help of Dr Simone Kosol in preparing the figures is highly appreciated.

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