Intrinsically unstructured proteins
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Intrinsically unstructured proteins, often referred to as naturally unfolded proteins, are proteins characterized by their lack of tertiary structure as isolated subunits. 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.
In the early days of structural biology, it was commonly believed that proteins had to be structured to be functional. The discovery of functional proteins that were intrinsically unfolded challenged this paradigm. The advent of structural genomics has been instrumental for the discovery of this new class of proteins, since traditional protein identification methods are biased towards well-structured proteins that occur in high concentration.
Many unstructured proteins seem to be involved in processes such as regulation of gene expression and the cell cycle. Often the proteins fold upon binding to their physiological partners; for example, the strong electric field and hydrogen bonding of a nucleic acid may stabilize the folded form of a transcription factor that would not be stable in isolation. Other unstructured proteins may function as flexible linkers, or as an easily digested source of amino acids (cf. casein).
Unstructured proteins will not crystallize, so it is not possible to characterize their residual structure by X-ray crystallography. Hence, the primary method to study such structure at high resolution is NMR spectroscopy.
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, 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
Intrinsically unfolded proteins tend to be more polar than most proteins and several computational methods have been developed to use this tendency to predict whether a given protein sequence is likely to be disordered. Examples of such methods are the PONDR method of Dunker and colleagues, the DISOPRED method of Jones and colleagues, and the DisEMBL method of Russell and colleagues.
References
- "Intrinsically unstructured proteins and their functions", HJ Dyson & PE Wright, Nat Rev Mol Cell Biol. 2005 Mar;6(3):197-208. Entrez PubMed [15738986]
- Li X, Romero P, Rani M, Dunker AK, and Obradovic Z. (1999) "Predicting Protein Disorder for N-, C-, and Internal Regions", Genome Informatics, 10, 30-40. Entrez PubMed [11072340]
- Ward JJ, Sodhi JS, McGuffin LJ, Buxton BF and Jones DT. (2004) "Prediction and functional analysis of native disorder in proteins from the three kingdoms of life", J. Mol. Biol., 337, 635-645. Entrez PubMed [15019783]
- Linding R, Jensen LJ, Diella F, Bork P, Gibson TJ, and Russell RB. (2003) "Protein disorder prediction: implications for structural proteomics", Structure, 11, 1316-1317. Entrez PubMed [14604535]
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