Intrinsically unstructured proteins and their functions

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Abstract
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.