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Intrinsically unstructured proteins
Intrinsically unstructured proteins, often referred to as naturally unfolded proteins or disordered proteins, are proteins characterized by their lack of stable tertiary structure as isolated subunits. The discovery of intrinsically unfolded proteins challenged the traditional protein structure paradigm, which states that a specific well-defined structure was required for the correct function of a protein and that the structure defines the function of the protein. This is clearly not the case for intrinsically unfolded proteins that remain functional despite the lack of a well-defined structure.
Additional recommended knowledge
Biological role of intrinsic disorder
Bioinformatic studies predict that a significant fraction of the genome codes for unstructured proteins, and that the fraction increases with the complexity of the organism (Ward et al, 2004). Many unstructured proteins seem to be involved in processes such as transcriptional regulation, translation and cellular signal transduction. It has also been reported that proteins associated with cancer have an increased propensity for intrinsic disorder (Iakoucheva et al, 2002).
Many disordered proteins have the binding affinity with their receptors regulated by post-translational modification, thus it has been proposed that the flexibility of disordered proteins facilitates the different conformational requirements for binding the modifying enzymes as well as their receptors.
Disordered regions are often found as flexible linkers connecting two globular domains. Linker sequences vary greatly in length and amino acid sequence, but are similar in amino acid composition (rich in polar uncharged amino acids). Flexible linkers allow the connecting domains to freely search the conformational space and to recruit their binding partners.
Coupled folding and binding
Many unstructured proteins undergo transitions to more ordered states upon binding to their targets. The coupled folding and binding may be locally, involving only a few interacting residues, or it might involve an entire protein domain. It was recently shown that the coupled folding and binding allows the burial of a large surface area that would only be possible for a fully structured proteins if they were much larger (Gunasekaran et al, 2003).
The ability of disordered proteins to bind, and thus to exert a function, shows that stability is not a required condition.
Sequence signatures of disorder
Intrinsically unstructured proteins are characterized by a low content of bulky hydrophobic amino acids and a high proportion of polar and charged amino acids. Thus disordered sequences cannot bury sufficient hydrophobic core to fold like stable globular proteins. In some cases, hydrophobic clusters in disordered sequences provide the clues for identifying the regions that undergo coupled folding and binding.
Many disordered proteins also reveal low complexity sequences, i.e. sequences with overrepresentation of a few residues. While low complexity sequences are a strong indication of disorder, the reverse is not necessarily true, that is, not all disordered proteins have low complexity sequences.
Disordered proteins have a low content of predicted secondary structure.
Identification of intrinsically unstructured proteins
Intrinsically unfolded proteins, once purified, can be identified by various experimental methods. Folded proteins have a high density (partial specific volume of 0.72-0.74 mL/g) and commensurately small radius of gyration. Hence, unfolded proteins can be detected by methods that are sensitive to molecular size, density or hydrodynamic drag, such as size exclusion chromatography, analytical ultracentrifugation, Small angle X-ray scattering (SAXS), and measurements of the diffusion constant. Unfolded proteins are also characterized by their lack of secondary structure, as assessed by far-UV (170-250 nm) circular dichroism (esp. a pronounced minimum at ~200 nm) or infrared spectroscopy.
Unfolded proteins have exposed backbone peptide groups exposed to solvent, so that they are readily cleaved by proteases, undergo rapid hydrogen-deuterium exchange and exhibit a small dispersion (<1 ppm) in their 1H amide chemical shifts as measured by NMR. (Folded proteins typically show dispersions as large as 5 ppm for the amide protons.)
De novo prediction of intrinsically unstructured proteins
Computational methods exploit the sequence signatures of disorder to predict whether a protein is disordered given its amino acid sequence. The table below, adapted from (Ferron et. al, 2006), shows the main features of softwares for disorder prediction. Note that different softwares use different definitions of disorder.
Since the methods above use different definitions of disorder and they were trained on different datasets, it is difficult to estimate their relative accuracy.
Disorder prediction methods
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Intrinsically_unstructured_proteins". A list of authors is available in Wikipedia.|