The rules of disorder or why disorder rules

The finding that a large fraction of proteins (over 30%) in eukaryotic cells lack a unique three-dimensional structure but are functional has forced the scientific community to review its understanding of the structure-function paradigm. The involvement of many of these intrinsically unstructured proteins (IUPs) in intracellular signalling and regulatory processes as well as their central positioning (as interaction hubs) in recently mapped protein interaction networks is particularly intriguing. Here, we review the functional and structural properties of IUPs such as (i) their facilitated regulation via diverse post-translational modifications of specific amino acids (ii) scaffolding and recruitment of different binding partners in space and time via the fly-casting mechanism, through peptide motifs and by coupling folding with binding and (iii) conformational variability and adaptability. All of these properties allow these proteins to hold key positions in cellular organisation and regulation which in turn make them tractable as drug targets. In addition, we discuss how such properties, individually and in combination, facilitate combinatorial regulation and re-use of the same component in multiple biological processes. (C) 2009 Elsevier Ltd. All rights reserved.