The interplay between structure and function in intrinsically unstructured proteins

AbstractIntrinsically unstructured proteins (IUPs) are common in various proteomes and occupy a unique structural and functional niche in which function is directly linked to structural disorder. The evidence that these proteins exist without a well-defined folded structure in vitro is compelling, and justifies considering them a separate class within the protein world. In this paper, novel advances in the rapidly advancing field of IUPs are reviewed, with the major attention directed to the evidence of their unfolded character in vivo, the interplay of their residual structure and their various functional modes and the functional benefits their malleable structural state provides. Via all these details, it is demonstrated that in only a couple of years after its conception, the idea of protein disorder has already come of age and transformed our basic concepts of protein structure and function

Structural Disorder in Eukaryotes

Based on early bioinformatic studies on a handful of species, the frequency of structural disorder of proteins is generally thought to be much higher in eukaryotes than in prokaryotes. To refine this view, we present here a comparative prediction study and analysis of 194 fully described eukaryotic proteomes and 87 reference prokaryotes for structural disorder. We found that structural disorder does distinguish eukaryotes from prokaryotes, but its frequency spans a very wide range in the two superkingdoms that largely overlap. The number of disordered binding regions and different Pfam domain types also contribute to distinguish eukaryotes from prokaryotes. Unexpectedly, the highest levels – and highest variability – of predicted disorder is found in protists, i.e. single-celled eukaryotes, often surpassing more complex eukaryote organisms, plants and animals. This trend contrasts with that of the number of domain types, which increases rather monotonously toward more complex organisms. The level of structural disorder appears to be strongly correlated with lifestyle, because some obligate intracellular parasites and endosymbionts have the lowest levels, whereas host-changing parasites have the highest level of predicted disorder. We conclude that protists have been the evolutionary hot-bed of experimentation with structural disorder, in a period when structural disorder was actively invented and the major functional classes of disordered proteins established

Exon-phase symmetry and intrinsic structural disorder promote modular evolution in the human genome

A key signature of module exchange in the genome is phase symmetry of exons, suggestive of exon shuffling events that occurred without disrupting translation reading frame. At the protein level, intrinsic structural disorder may be another key element because disordered regions often serve as functional elements that can be effectively integrated into a protein structure. Therefore, we asked whether exon-phase symmetry in the human genome and structural disorder in the human proteome are connected, signalling such evolutionary mechanisms in the assembly of multi-exon genes. We found an elevated level of structural disorder of regions encoded by symmetric exons and a preferred symmetry of exons encoding for mostly disordered regions (>70% predicted disorder). Alternatively spliced symmetric exons tend to correspond to the most disordered regions. The genes of mostly disordered proteins (>70% predicted disorder) tend to be assembled from symmetric exons, which often arise by internal tandem duplications. Preponderance of certain types of short motifs (e.g. SH3-binding motif) and domains (e.g. high-mobility group domains) suggests that certain disordered modules have been particularly effective in exon-shuffling events. Our observations suggest that structural disorder has facilitated modular assembly of complex genes in evolution of the human genome. © 2013 The Author(s)

Structural disorder promotes assembly of protein complexes

<p>Abstract</p> <p>Background</p> <p>The idea that the assembly of protein complexes is linked with protein disorder has been inferred from a few large complexes, such as the viral capsid or bacterial flagellar system, only. The relationship, which suggests that larger complexes have more disorder, has never been systematically tested. The recent high-throughput analyses of protein-protein interactions and protein complexes in the cell generated data that enable to address this issue by bioinformatic means.</p> <p>Results</p> <p>In this work we predicted structural disorder for both <it>E. coli </it>and <it>S. cerevisiae</it>, and correlated it with the size of complexes. Using IUPred to predict the disorder for each complex, we found a statistically significant correlation between disorder and the number of proteins assembled into complexes. The distribution of disorder has a median value of 10% in yeast for complexes of 2–4 components (6% in <it>E. coli</it>), but 18% for complexes in the size range of 11–100 proteins (12% in <it>E. coli</it>). The level of disorder as assessed for regions longer than 30 consecutive disordered residues shows an even stronger division between small and large complexes (median values about 4% for complexes of 2–4 components, but 12% for complexes of 11–100 components in yeast). The predicted correlation is also supported by experimental evidence, by observing the structural disorder in protein components of complexes that can be found in the Protein Data Bank (median values 1. 5% for complexes of 2–4 components, and 9.6% for complexes of 11–100 components in yeast). Further analysis shows that this correlation is not directly linked with the increased disorder in hub proteins, but reflects a genuine systemic property of the proteins that make up the complexes.</p> <p>Conclusion</p> <p>Overall, it is suggested and discussed that the assembly of protein-protein complexes is enabled and probably promoted by protein disorder.</p

Targeting LLPS in disease: a new modality in drug development

Biomolecular condensation is a process whereby many macromolecules (proteins and RNAs) form non-stoichiometric, functional assemblies. The dominant mechanism of such biomolecular condensation is liquid-liquid phase separation (LLPS), which leads to the formation of membraneless organelles (MLOs), such as the nucleolus and stress granules, in the cell. The proteins involved often have a high proportion of intrinsic structural disorder, which drive LLPS by transient, multivalent interactions. As MLOs play key roles in cell signaling, the misregulation of their formation and dissolution often leads to diseases termed “condensatopathies”. In my presentation, I will outline the basic mechanisms leading to such disease states, focusing on cancer, viral infections and neurodegeneration. I will also discuss the different potential strategies for correcting these errors in cell signaling, and show through specific examples how drug candidates, “c-mods” capable of correcting MLO misregulation, can be developed.Book of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 202

Structural characterization of intrinsically disordered proteins by NMR spectroscopy.

Recent advances in NMR methodology and techniques allow the structural investigation of biomolecules of increasing size with atomic resolution. NMR spectroscopy is especially well-suited for the study of intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) which are in general highly flexible and do not have a well-defined secondary or tertiary structure under functional conditions. In the last decade, the important role of IDPs in many essential cellular processes has become more evident as the lack of a stable tertiary structure of many protagonists in signal transduction, transcription regulation and cell-cycle regulation has been discovered. The growing demand for structural data of IDPs required the development and adaption of methods such as 13C-direct detected experiments, paramagnetic relaxation enhancements (PREs) or residual dipolar couplings (RDCs) for the study of 'unstructured' molecules in vitro and in-cell. The information obtained by NMR can be processed with novel computational tools to generate conformational ensembles that visualize the conformations IDPs sample under functional conditions. Here, we address NMR experiments and strategies that enable the generation of detailed structural models of IDPs

Individual, occupational, and workplace correlates of occupational health and safety vulnerability in a sample of Canadian workers

Objective: To describe OH&amp;S vulnerability across a diverse sample of Canadian workers.Methods: A survey was administered to 1,835 workers employed more than 15 hrs/week in workplaces with at least five employees. Adjusted logistic models were fitted for three specific and one overall measure of workplace vulnerability developed based on hazard exposure and access to protective OH&amp;S policies and procedures, awareness of employment rights and responsibilities, and workplace empowerment.Results: More than one third of the sample experienced some OH&amp;S vulnerability. The type and magnitude of vulnerability varied by labor market sub-group. Younger workers and those in smaller workplaces experienced signficantly higher odds of multiple types of vulnerability. Temporary workers reported elevated odds of overall, awareness- and empowerment-related vulnerability, while respondents born outside of Canada had significantly higher odds of awareness vulnerability.Conclusion: Knowing how labor market sub-groups experience different types of vulnerability can inform better-tailored primary prevention interventions.<br /