Pathological unfoldomics of uncontrolled chaos: intrinsically disordered proteins and human diseases.

Many biologically important proteins lack stable tertiary and/or secondary structure under physiological conditions in vitro as a whole or in part.1–5 These intrinsically disordered proteins (IDPs), or intrinsically disordered protein regions (IDPRs) of hybrid proteins possessing both structured and disordered domains, do not have unique well-defined 3D structures, existing instead as collapsed or extended dynamically mobile conformational ensembles. Therefore, natural proteins can be found in one of three major protein forms: functional and folded, nonfunctional and misfolded, or functional and intrinsically disordered. Although IDPs and IDPRs are highly dynamic, their structures can be described reasonably well by a rather limited number of lower-energy conformations.6,7 The structural plasticity and conformational adaptability of IDPs/IDPRs and their intrinsic lack of rigid structure leads to a number of exceptional functional advantages, providing them with unique capabilities to act in functional modes not achievable by ordered proteins.5 As a result, intrinsic disorder is a common feature of proteins involved in signaling, regulation, and recognition, and IDPs/IDPRs play diverse roles in modulation and control of their binding partners’ functions and in promoting the assembly of supramolecular complexes. The biological actions of IDPs/IDPRs, which frequently serve as major regulators of their binding partners, are controlled by extensive posttranslational modifications (PTMs), such as phosphorylation, acetylation, ubiquitination, and sumoylation,5 and by alternative splicing.8 In fact, many IDPs/IDPRs are known to contain multiple functional elements that contribute to their ability to be involved in interaction with, regulation of, and control by multiple structurally unrelated partners.9 Given the existence of multiple functions in a single disordered protein, and given that each functional element is typically relatively short, alternative splicing could readily generate sets of protein isoforms with highly diverse regulatory elements.8 The complexity of the disorder-based interactomes is further increased by the capacity of a single IDPR to bind to multiple partners, gaining very different structures in the bound state.10 IDPs can form highly stable complexes or be involved in signaling interactions where they undergo constant “bound–unbound” transitions, thus acting as dynamic and sensitive “on–off” switches. The ability of these proteins to return to highly flexible conformations after the completion of a particular function, and their predisposition to adopt different conformations depending on their environment, are unique physiological properties of IDPs that allow them to exert different functions in different cellular contexts according to a specific conformational state.5 Although the field of protein disorder has started from careful analysis of a very limited number of biologically active proteins without unique structures (which, for a long time, were taken as rare exceptions from the general “one sequence–one unique structure–one unique function” paradigm),1–4 applications of various disorder predictors to different proteomes revealed that IDPs are highly abundant in nature,11–16 and the overall amount of disorder in proteins increases from bacteria to archaea to eukaryota, with over half of all eukaryotic proteins predicted to contain extended IDPRs.11,12,15–17 One explanation for this trend is a change in the cellular requirements for certain protein functions, particularly cellular signaling. In support of this hypothesis, an analysis of a eukaryotic signal protein database indicated that the majority of known signal transduction proteins were predicted to contain significant regions of disorder.18 A detailed study focused on the intricate mechanisms of IDP regulation inside the cell was recently conducted by Gsponer et al.19 These authors grouped all the Saccharomyces cerevisiae proteins into three classes according to their predicted disorder propensities and evaluated the correlations between intrinsic disorder and the various regulation steps of protein synthesis and degradation.19 Although the transcriptional rates of mRNAs encoding IDPs and ordered proteins were comparable, IDP-encoding transcripts were generally less abundant than transcripts encoding ordered proteins because of increased decay rates of IDP mRNAs.19 Also, IDPs were found to be less abundant than ordered proteins because of lower rates of protein synthesis and shorter protein half-lives.19 Curiously, IDPs were shown to be substrates of twice as many kinases as ordered proteins. Furthermore, the vast majority of kinases whose substrates were IDPs were either regulated in a cell-cycle-dependent manner or activated upon exposure to specific stimuli or stress.19 Similar regulation trends were also found in proteomes of Schizosaccharomyces pombe and Homo sapiens,19 suggesting that both unicellular and multicellular organisms use evolutionarily conserved mechanisms to regulate the availability of their IDPs. This tight regulation is directly related to the major roles of IDPs/IDPRs in signaling, where it is crucial for a given protein to be available in appropriate amounts and not to be present longer than needed.19 It was also pointed out5 that although the abundance of many IDPs may be closely regulated, some disordered proteins could be present in cells in large amounts or/and for long periods of time, either due to specific PTMs or via interactions with other factors. These events could promote changes in cellular localization of IDPs or protect them from degradation.3,20–23 Taken together, these data highlight that the chaos seemingly associated with highly flexible and promiscuous IDPs/IDPRs is under tight control.24