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REVIEWS The occurrence of unstructured regions of significant size (>50 residues) is surprisingly common in func- tional proteins 1,2 .In addition, the existence of functional unstructured proteins — for example, polypeptide hormones 3 — has been recognized for many years, and unstructured proteins were observed in intact cells in early proton NMR experiments 4 .However, the func- tional role of intrinsically disordered proteins in crucial areas such as transcriptional regulation, translation and cellular signal transduction 5–8 has only recently been recognized, as a consequence of the use of new paradigms in biochemical methodology. In particular, the availability of large amounts of sequence data cou- pled with gene-based functional analysis (BOX 1) has led to the extensive use of sequence analysis for the identification of intrinsically unstructured sequences. Another reason for the attention being paid to disor- dered regions of proteins is that techniques have recently been developed to analyse their structural propensities in solution. Crystal-structure analysis cannot provide information on unstructured states — it can only indicate their presence through the absence of electron density in local regions. However, spectroscopic methods such as NMR have now advanced in sensitivity and resolution, to the point at which the structural propensities and dynamics of sizeable disordered proteins in solution can be thoroughly characterized. This review focuses on the identification of intrinsi- cally unstructured proteins and describes their general characteristics. The functional roles that unstructured regions can have are summarized in the context of published examples, including several from the tran- scriptional activator cyclic-AMP-response-element- binding protein ( CREB )-binding protein ( CBP ). Furthermore, the article also discusses the advantages and thermodynamic and biological consequences of the presence, in certain cellular machines, of regions that fold on binding to their physiological target or that function as flexible linkers. Will a domain be folded or unfolded? Predicting the three-dimensional (3D) structures of globular proteins from sequence data alone remains a key challenge, except in situations in which the protein has a high sequence homology to domains of known structure. On the other hand, identifying sequences that are likely to be intrinsically disordered — that is, that do not fold spontaneously into well-organized globular structures in the absence of stabilizing interactions — is comparatively straightforward. Sequence signatures of intrinsic disorder. A signature of probable intrinsic disorder is the presence of low sequence complexity and amino-acid compositional bias, with a low content of bulky hydrophobic amino INTRINSICALLY UNSTRUCTURED PROTEINS AND THEIR FUNCTIONS H. Jane Dyson and Peter E. Wright Abstract | Many gene sequences in eukaryotic genomes encode entire proteins or large segments of proteins that lack a well-structured three-dimensional fold. Disordered regions
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This note was uploaded on 05/28/2010 for the course WE BIBI010000 taught by Professor Marnikvuylsteke during the Spring '10 term at Ghent University.

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