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Intrinsically disordered proteins in cellular signalling and regulation

Key Points

  • Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) of proteins that may also contain structured domains mediate crucial signalling processes in eukaryotic cells.

  • Disorder is advantageous in cell signalling because disordered sequences have the potential to bind to multiple partners, often using different structures.

  • Disordered regions are relatively accessible, often contain multiple binding motifs and are frequently the sites for post-translational modification, an important mediator of the control of signalling pathways.

  • Disordered proteins have central roles in the formation of higher-order signalling assemblies and in the operation of circadian clocks.

Abstract

Intrinsically disordered proteins (IDPs) are important components of the cellular signalling machinery, allowing the same polypeptide to undertake different interactions with different consequences. IDPs are subject to combinatorial post-translational modifications and alternative splicing, adding complexity to regulatory networks and providing a mechanism for tissue-specific signalling. These proteins participate in the assembly of signalling complexes and in the dynamic self-assembly of membrane-less nuclear and cytoplasmic organelles. Experimental, computational and bioinformatic analyses combine to identify and characterize disordered regions of proteins, leading to a greater appreciation of their widespread roles in biological processes.

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Figure 1: Intrinsic disorder in signalling.
Figure 2: Variable binding affinities of IDPs.
Figure 3: Response to multisite phosphorylation in intrinsically disordered regions.
Figure 4: Autoinhibition through interactions with intrinsically disordered regions.
Figure 5: Disorder mediates stress-induced translational silencing.

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Acknowledgements

The authors apologize to the many colleagues whose work could not be cited owing to space limitations. Work in the authors' laboratories was supported by grants CA096865 (P.E.W.) and GM71862 (H.J.D.) from the US National Institutes of Health and by the Skaggs Institute for Chemical Biology (P.E.W.).

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Correspondence to Peter E. Wright or H. Jane Dyson.

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DATABASES

Database of Disordered Protein Prediction (D2P2)

DisProt database

Protein Ensemble Database (pE-DB)

RCSB Protein Data Bank

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Glossary

Association rates

The speeds with which complexes are created from their component parts. The speed of the reverse process, detachment of the components, is known as the dissociation rate. The binding affinity is determined by the relative magnitude of the association and dissociation rates; for example, a fast association rate ('on-rate') and a slow dissociation rate ('off-rate') is characteristic of a high-affinity complex.

Conformational ensembles

Structural descriptions of proteins that do not have a single, well-ordered three-dimensional structure. Conformational ensembles contain a multitude of different interconverting structures, which, when averaged, are consistent with observed parameters, such as nuclear magnetic resonance (NMR) spectra or small-angle X-ray scattering data.

Binding free energy

The difference in free energy (ΔG) between the free and bound states of a complex. If the complex is stable, the binding free energy is negative.

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Wright, P., Dyson, H. Intrinsically disordered proteins in cellular signalling and regulation. Nat Rev Mol Cell Biol 16, 18–29 (2015). https://doi.org/10.1038/nrm3920

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