Intrinsically unstructured proteins: Re-assessing the protein structure-function paradigm

A major challenge in the post-genome era will be determination of the funct ions of the encoded protein sequences. Since it is generally assumed that t he function of a protein is closely linked to its three-dimensional structu re, prediction or experimental determination of the library of protein stru ctures is a matter of :high priority. However, a large proportion of gene s equences appear to;code not for folded, globular proteins, but for long str etches of amino acids that are likely to be either unfolded in solution or adopt non-globular structures of unknown conformation. Characterization of the conformational propensities and function of the non-globular protein se quences represents a major challenge. The high proportion of these sequence s in the genomes of all organisms studied to date argues for important, as yet unknown functions,since there could be no other reason for their persis tence throughout evolution. Clearly the assumption that a folded three-dime nsional: structure is necessary-for function needs to be re-examined. Altho ugh the functions of many proteins are directly related to their three-dime nsional structures, numerous proteins that lack intrinsic globular structur e under; physiological conditions have now been recognized. Such proteins a re frequently involved in some of the most important regulatory functions i n the cell, and the lack of intrinsic structure in:many cases is relieved w hen:the protein binds to its target molecule. The intrinsic lack of structu re can confer functional advantages on a protein, including the ability to bind to several different targets. It also allows precise control over the thermodynamics of the binding process: and provides a simple mechanism for inducibility by phosphorylation or through interaction with other component s of the cellular machinery. Numerous examples of domains that are unstruct ured in solution but which become structured upon binding to the target hav e been noted in the areas of cell cycle control and both transcriptional an d translational regulation, and unstructured domains are present in protein s that are targeted for rapid destruction.:Since such proteins participate in critical cellular control mechanisms, it appears Likely that their rapid turnover,: aided by their unstructured nature in the unbound state, provid es a-level of control that allows rapid and accurate responses of the cell to changing environmental conditions. (C) 1999 Academic Press.