Disorder in Protein Structure and Function - Session Introduction

It is commonly assumed that a protein must attain a stable, folded conformation in order to carry out its specific biological function. Not all proteins conform to this simple view of protein structure and function, however. Certain regions within proteins, and in some cases entire proteins, are not ordered into a unique tertiary structure, but instead appear to exist as ensembles of structures. Protein structures determined by X-ray crystallography and NMR have revealed numerous such disordered regions, some of them quite extensive. Recent progress in predicting regions of disorder from amino acid sequence has provided evidence that these regions occur in nature with an unexpectedly high frequency 1. There is now a growing awareness of the fundamental importance of disordered protein sequences in many biological processes. Disordered protein sequences function in some cases to mechanically uncouple structured domains, making their dynamics less constrained. Linkers of this type are important in a diverse collection of proteins, from viral attachment proteins to transcription factors. Disordered regions also provide access for protease digestion, which is critical for the regulation of many important cellular processes. Disorder-to-order transitions in proteins may be one of the major factors in biomechanics, for example in the development of force by protein assemblies. Disorder-to-order transitions may have a crucial role to play in macromolecular recognition. There are numerous examples of protein-protein, protein-nucleic acid, and protein-ligand interactions involving disordered protein segments. It has been postulated that disorder-to-order transitions provide a mechanism for uncoupling binding affinity and specificity 2 , thereby permitting weak but highly specific interactions, or conversely, strong but relatively nonspecific interactions.