Introduction to intrinsically disordered proteins (IDPs).


F more than a century, molecular and structural biology, biochemistry, and protein biophysics have been dominated by a “rigid” or “semi-rigid” view of a functional protein molecule or functional protein domain. These functional entities were assumed to possess unique and stable 3D structures, a view supported by numerous reports of protein structures determined using X-ray crystallography and NMR spectroscopy (as of May 27, 2014, there were 97,857 structures of proteins and protein-nucleic acid complexes in the Protein Data Bank, with 87,536 of these structures (89.5%) determined by X-ray crystallography). These experimentally determined structures depicted protein molecules as aperiodic crystals, in which both atoms and backbone Ramachandran angles are relatively fixed and possess low-amplitude thermal fluctuations around their equilibrium positions. Although the functions of many proteins clearly fit within this structure−function paradigm, where a unique amino acid sequence encodes a unique energetically stable 3D fold associated with conformational fluctuations that allow for unique biological function, recent studies have revealed that many functional proteins or functional protein regions do not have unique 3D structures under functional conditions. In fact, contrarily to the ordered proteins and domains, such biologically active intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) have no single, well-defined equilibrium structure and exist as highly dynamic, heterogeneous ensembles of conformers resulting from their relatively flat free-energy surface. These IDPs/IDPRs are highly abundant in nature and have numerous biological activities. The number of structurally and functionally characterized IDPs and IDPRs is growing rapidly. The dramatic increase in corresponding scientific literature is the reflection of the growing interest in this class of proteins. This point is illustrated by Figure 1, which shows that, starting from the turn of the century, the number of papers dealing with the different aspects of intrinsically disordered proteins is exponentially increasing. The number of citations of these papers is also exponentially increasing at an exceeding rate, clearly indicating that protein disorder−related research is under increasing demand. Although Figure 1 seems to suggest that IDPs and IDPRs were discovered quite recently, the reality is more complex, and biologically active proteins without stable structures were rediscovered multiple times, showing that the phenomenon of biological functionality without stable structure has been periodically reported during the last 75 years or so. For a long time, this phenomenon was unnoticed by a wide audience because these highly dynamic proteins or protein regions have, over the years, been discovered one by one and described in the literature by a plethora of different names. In other words, this complex and lengthy route to recognizing these proteins as a novel class left in its path a trail of terms used for their description, giving rise to the intricate “paleontology” of this phenomenon. An incomplete list of terms used in the literature to describe these proteins includes floppy, pliable, rheomorphic, flexible, mobile, partially folded, natively denatured, natively unfolded, natively disordered, intrinsically unstructured, intrinsically denatured, intrinsically unfolded, intrinsically disordered, vulnerable, chameleon, malleable, 4D, protein clouds, dancing proteins, proteins waiting for partners, 3 proteins, and several other names that represent different combinations of “natively/naturally/inherently/intrinsically” with “unfolded/unstructured/disordered/denatured/flexible” among several other terms. The lack of common terminology was clearly the major reason precluding the appearance of the idea that this class of proteins constitutes a separate and important extension to the protein kingdom. The situation has changed at the turn of the century, mostly due to the bioinformatics studies that came to the important conclusion that naturally flexible proteins, instead of just being rare exceptions, represent a very broad class of proteins, and the unstructural biology came of age. The rapidly growing interest in IDPs can be attributed to several factors. The first of them is the role these proteins play in changing the understanding of the molecular mechanisms of protein action and in reshaping the protein structure−function relationship. The discovery of biologically active but extremely flexible proteins questioned the assumption that unique 3D structure is a prerequisite for protein function. Although IDPs lack stable structures at functional conditions, they are known to carry out a number of crucial biological functions that are complementary to the functional repertoire of structured (ordered) proteins. In any given organism, IDPs constitute a functionally broad and densely populated subset of its

DOI: 10.1021/cr500288y

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@article{Uversky2014IntroductionTI, title={Introduction to intrinsically disordered proteins (IDPs).}, author={Vladimir N. Uversky}, journal={Chemical reviews}, year={2014}, volume={114 13}, pages={6557-60} }