Intrinsically unstructured proteins and their functions

Key Points

  • Recent advances in the techniques that are used to design and prepare protein domains have led to the realization that several proteins, which are involved in important cellular processes, contain regions that are intrinsically unstructured in their normal, functional state.

  • Disordered or unstructured regions are characterized by a compositional bias in their amino-acid sequence, in that they contain a significantly larger proportion of small and hydrophilic amino acids and proline residues than structured regions.

  • Sequences with extreme compositional bias generally function as linkers between structured domains and are frequently the sites of disease-related gene truncations or translocations.

  • The presence of unstructured or incompletely folded regions in proteins that are involved in signalling, transcriptional and translational processes can be rationalized in several ways — for example, the requirement for binding with high specificity and reversibility, the requirement for binding to different partners (for example, if post-translational modification is necessary for control of function), and the requirement for rapid degradation when the signal is turned off.

  • The folding of an unstructured domain on binding to its partner can result in the formation of a complex with an extremely large surface area of interaction. This provides a specificity that could not otherwise be obtained (except by increasing the size of the protein, with the consequent increases in metabolic burden on the cell).

  • The coupled folding and binding of proteins allows a much greater range of possible interactions within the same set of proteins, and therefore provides versatility. For example, different signalling proteins can bind to a given receptor, potentiating different reactions, and a given signalling protein can bind to different receptors.


Many gene sequences in eukaryotic genomes encode entire proteins or large segments of proteins that lack a well-structured three-dimensional fold. Disordered regions can be highly conserved between species in both composition and sequence and, contrary to the traditional view that protein function equates with a stable three-dimensional structure, disordered regions are often functional, in ways that we are only beginning to discover. Many disordered segments fold on binding to their biological targets (coupled folding and binding), whereas others constitute flexible linkers that have a role in the assembly of macromolecular arrays.

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Figure 1: The continuum of protein structure.
Figure 2: Structured and unstructured regions of CBP.
Figure 3: The structure of the TAZ1 domain in complex with two interaction domains.
Figure 4: The structure of a HIF1α-interaction-domain fragment bound to two targets.
Figure 5: The structure of a CBP-bromodomain–acetyl-lysine complex.

Accession codes


Protein Data Bank


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We would like to thank past and present members of our laboratories for their contributions to the ideas that are expressed in this review. We are particularly grateful to M. Martinez-Yamout for continuing important contributions and for critically reading the manuscript. Our work is supported by grants from the National Institutes of Health.

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Protein Data Bank























DisEMBL — Intrinsic Protein Disorder Prediction 1.4

DISPHOS 1.3 — Disorder-Enhanced Phosphorylation Sites Predictor

DISPROT — Database of Protein Disorder


GLOBPROT 2 — Intrinsic Protein Disorder, Domain & Globularity Prediction

PONDR (Predictors of Natural Disordered Regions)

The DISOPRED2 Disorder Prediction Server

The PredictProtein server



Nuclear magnetic resonance (NMR) spectroscopy provides information on the three-dimensional structure and dynamics of biological molecules in solution.


The ultraviolet circular-dichroism spectrum uses the chirality or 'handedness' of biological molecules to provide information on secondary structure in solution.


Fluorescence spectroscopy of proteins gives information on the environment of aromatic rings, and can be used in conjunction with external probes to determine the distances between atoms in a molecule.


Vibrational circular dichroism (CD) is the chiroptical version of infra-red spectroscopy, and it gives information on the vibrations of individual bonds in a molecule.


Raman spectroscopy provides information on bond vibrations that is complementary to that provided by infra-red spectroscopy.


The molten globule was originally defined with reference to the folding pathway of an ordered protein as a compact state of a protein, with native-like secondary structure but disordered tertiary structure.


In terms of their structure, proteins can be defined as being in one of three states — unfolded, molten globule or folded.


This term refers to a 'statistical coil' with a random distribution of dihedral angles. In practice, no protein is ever a completely random coil, but the term is a convenient shorthand for the ensemble of conformations that occur for an unfolded protein.


A similar division for protein structure as the protein trinity, but the quartet includes a pre-molten globule state as well as the unfolded, molten-globule and folded states.


A plot of the backbone dihedral angles φ and ψ for a polypeptide chain. Areas of low energy (greater probability) encompass angles that are observed in α-helical and β-sheet structures, and a part of the broad β-minimum is defined as the 'polyproline II' region.


The Cys2His2 zinc finger is a common structural motif. It is a small sequence motif that contains two Cys and two His residues, which coordinate a single zinc ion. Tandem repeats of zinc fingers are common.


The Src-homology-2 (SH2) domain, which is a peptide-binding domain of Src protein kinases, is a common structural motif. It binds peptides and proteins that contain phosphorylated Tyr residues.


The Src-homology-3 domain, which is a peptide-binding domain of Src protein kinases, is a common structural motif. It binds polyproline sequences.


Sequences, or genes, that have originated from a common ancestral sequence, or gene, by a duplication event.


A Ca2+-binding membrane protein that mediates homophilic cell adhesion.


E3 (enzyme-3) ubiquitin ligases are the enzymes that are responsible for attaching ubiquitin to proteins, which can target them for destruction by the 26S proteasome.


A folded protein with a stable three-dimensional structure unfolds cooperatively on addition of denaturant — that is, all of the molecules in the ensemble change from being fully folded to fully unfolded within a small range of denaturant concentration. This produces the sigmoidal unfolding curve that is typical for a folded protein.


During thermal denaturation, a folded protein shows a typical bell-shaped transition in the plot of heat capacity versus temperature (measured, for example, by differential scanning calorimetry). Unfolded proteins do not show this behaviour.


(small ubiquitin-like modifier). SUMO proteins are ubiquitin-like proteins that post-translationally modify proteins to control their localization and activity.


Refers to the targeting of proteins for destruction by the 26S proteasome through the attachment of ubiquitin.


This term refers to an amino-acid sequence that is enriched in Pro (P), Glu (E), Ser (S) and Thr (T) residues. PEST domains are frequently found in signalling, regulatory and adhesion molecules.


This term refers to the group of, frequently genetic, diseases that arise due to the expansion of regions of repeated glutamine sequences — for example, Huntington's disease.

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Dyson, H., Wright, P. Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 6, 197–208 (2005).

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