Intrinsically Disordered Proteins


Intrinsically disordered proteins (IDPs) represent a growing category of proteins, especially in the eukaryotic proteomes. They are linked to a wide variety of biological functions, including those which are commonly impaired in cancer and neurodegenerative diseases. Since IDPs by definition do not adopt a well‐defined native structure in solution but exist as an ensemble of rapidly interconverting conformations, their structural characterisation is highly challenging. However, a large body of evidence accumulated mainly through nuclear magnetic resonance spectroscopy and small‐angle X‐ray scattering techniques indicates that IDPs are far from the statistical random coil polypeptide chains such as chemically denatured proteins, but exhibit a rich diversity of transient local and long‐range structural propensities. Such structural preferences are likely to be of functional importance and may be considered as potential drug targets.

Key Concepts:

  • A large proportion of proteins, especially in eukaryotic proteomes, do not adopt a well‐ordered structure in near‐physiologic conditions.

  • The classical tenet of biochemistry, the so‐called ‘structure–function paradigm’, that proteins need to have a well‐ordered structure to be functional, presents a restricted view. Instead, a wide variety of proteins from highly structured to almost completely unstructured ones play functional roles in biological systems.

  • Intrinsically disordered proteins play crucial roles in cellular processes as diverse as signalling, cell cycle control, molecular recognition, transcription, replication and chaperoning. Accordingly, they are closely linked to pathologic states such as cancer and neurodegenerative disorders.

  • Biophysical techniques, in particular NMR spectroscopy, SAXS and single‐molecule fluorescence measurements, provide detailed insight into the conformations populated by intrinsically disordered proteins.

  • The intrinsically disordered proteins are not like statistical coil‐like polypeptide chains, but show local and even long‐range structural preferences.

  • The ‘ensemble view’ of intrinsically disordered proteins resolves the ‘reconciliation problem’, the apparent inconsistence between their coil‐like hydrodynamic behaviour and presence of secondary and even tertiary contacts.

  • A more‐detailed structural knowledge of intrinsically disordered proteins might provide a basis for rational drug design against them.

Keywords: intrinsically disordered protein; intrinsically unstructured protein; natively unfolded protein; pre‐molten globule; random coil; entropic chain; NMR spectroscopy; SAXS; single‐molecule FRET; tau

Figure 1.

Six functional classes of intrinsically disordered proteins (IDPs). For the ‘entropic chains’, protein function directly depends on protein disorder. For the other five classes, the function of the IDP relies on a temporary or permanent binding to one or more partner molecules. See the text and the references for a more detailed description and examples of each class.

Figure 2.

The protein quartet model, stating that functions of proteins originate not exclusively from well‐ordered conformations, but arise from four conformational states of the polypeptide chain, specified as well‐ordered, molten‐globule, pre‐molten globule and random coil, and transitions between any of them.

Figure 3.

Two‐dimensional 1H,15N HSQC spectra of htau40 with the spin label MTSL (shown on top) attached to a single cysteine at position 178. HSQC spectra of the paramagnetic (blue) and diamagnetic (red) states are shown. The diamagnetic state was obtained by reduction of MTSL with ascorbic acid. Residue A173, which is in close spatial proximity to the paramagnetic centre, reveals a remarkable intensity decrease due to paramagnetic relaxation enhancement. Other peaks show different levels of paramagnetic broadening, depending on the distance of their corresponding amide proton from the paramagnetic centre.

Figure 4.

Representation of the conformations of full‐length human tau protein (htau40, 441 residues) calculated using a large number of distance restraints, which were obtained from paramagnetic broadening effects. Colour coding follows the secondary structure propensities in the tau protein – that is, α‐helical, β‐structure and polyproline‐II stretches are depicted in red, yellow and green, respectively. Reprinted with permission from Mukrasch et al. .



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Further Reading

Eliezer D (2007) Characterizing residual structure in disordered protein states using nuclear magnetic resonance. Methods in Molecular Biology 350: 49–67.

Ferreon AC, Moran CR, Gambin Y et al. (2010) Single‐molecule fluorescence studies of intrinsically disordered proteins. Methods in Molecular Biology 472: 179–204.

Jensen MR, Markwick PR, Meier S et al. (2009) Quantitative determination of the conformational properties of partially folded and intrinsically disordered proteins using NMR dipolar couplings. Structure 17(9): 1169–1185.

Mertens HD and Svergun DI (2010) Structural characterization of proteins and complexes using small‐angle X‐ray solution scattering. Journal of Structural Biology 172(1): 128–141.

Shi Z, Chen K, Liu Z et al. (2006) Conformation of the backbone in unfolded proteins. Chemical Reviews 106(5): 1877–1897.

Tompa P (2009) Structure and Function of Intrinsically Disordered Proteins, 1st edn. Florida: Chapman & Hall/CRC Press.

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Rezaei‐Ghaleh, Nasrollah, and Zweckstetter, Markus(Sep 2011) Intrinsically Disordered Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023212]