The evolving world of pseudoenzymes: proteins, prejudice and zombies.
Ontology highlight
ABSTRACT:
SUBMITTER: Eyers PA
PROVIDER: S-EPMC5106787 | biostudies-literature | 2016 Nov
REPOSITORIES: biostudies-literature
Publications
The evolving world of pseudoenzymes: proteins, prejudice and zombies.
Eyers Patrick A PA Murphy James M JM
BMC biology 20161111 1
Pseudoenzymes are catalytically deficient variants of enzymes that are represented in all major enzyme families. Their regulatory functions in signalling pathways are shedding new light on the non-catalytic functions of active enzymes, and are suggesting new ways to target cellular signalling mechanisms with drugs. ...[more]
Similar Datasets
Project description:Punishment offers a powerful mechanism for the maintenance of cooperation in human and animal societies, but the maintenance of costly punishment itself remains problematic. Game theory has shown that corruption, where punishers can defect without being punished themselves, may sustain cooperation. However, in many human societies and some insect ones, high levels of cooperation coexist with low levels of corruption, and such societies show greater wellbeing than societies with high corruption. Here we show that small payments from cooperators to punishers can destabilize corrupt societies and lead to the spread of punishment without corruption (righteousness). Righteousness can prevail even in the face of persistent power inequalities. The resultant righteous societies are highly stable and have higher wellbeing than corrupt ones. This result may help to explain the persistence of costly punishing behavior, and indicates that corruption is a sub-optimal tool for maintaining cooperation in human societies.
| S-EPMC3440392 | biostudies-literature
Project description:Pseudoenzymes are emerging as significant mediators and regulators of signal transduction. These proteins maintain enzyme folds and topologies, but are disrupted in the conserved motifs required for enzymatic activity. Among the pseudoenzymes, the pseudoGTPase group of atypical GTPases has recently expanded and includes the Rnd and RGK groups, RhoH and the RhoBTB proteins, mitochondrial RhoGTPase and centaurin-γ groups, CENP-M, dynein LIC, Entamoeba histolytica RabX3, leucine-rich repeat kinase 2, and the p190RhoGAP proteins. The wide range of cellular functions associated with pseudoGTPases includes cell migration and adhesion, membrane trafficking and cargo transport, mitosis, mitochondrial activity, transcriptional control, and autophagy, placing the group in an expanding portfolio of signaling pathways. In this review, we examine how the pseudoGTPases differ from canonical GTPases and consider their mechanistic and functional roles in signal transduction. We review the amino acid differences between the pseudoGTPases and discuss how these proteins can be classified based on their ability to bind nucleotide and their enzymatic activity. We discuss the molecular and structural consequences of amino acid divergence from canonical GTPases and use comparison with the well-studied pseudokinases to illustrate the classifications. PseudoGTPases are fast becoming recognized as important mechanistic components in a range of cellular roles, and we provide a concise discussion of the currently identified members of this group. ENZYMES: small GTPases; EC number: EC 3.6.5.2.
| S-EPMC7544640 | biostudies-literature
Project description:BackgroundClustering sequences into groups of putative homologs (families) is a critical first step in many areas of comparative biology and bioinformatics. The performance of clustering approaches in delineating biologically meaningful families depends strongly on characteristics of the data, including content bias and degree of divergence. New, highly scalable methods have recently been introduced to cluster the very large datasets being generated by next-generation sequencing technologies. However, there has been little systematic investigation of how characteristics of the data impact the performance of these approaches.ResultsUsing clusters from a manually curated dataset as reference, we examined the performance of a widely used graph-based Markov clustering algorithm (MCL) and a greedy heuristic approach (UCLUST) in delineating protein families coded by three sets of bacterial genomes of different G+C content. Both MCL and UCLUST generated clusters that are comparable to the reference sets at specific parameter settings, although UCLUST tends to under-cluster compositionally biased sequences (G+C content 33% and 66%). Using simulated data, we sought to assess the individual effects of sequence divergence, rate heterogeneity, and underlying G+C content. Performance decreased with increasing sequence divergence, decreasing among-site rate variation, and increasing G+C bias. Two MCL-based methods recovered the simulated families more accurately than did UCLUST. MCL using local alignment distances is more robust across the investigated range of sequence features than are greedy heuristics using distances based on global alignment.ConclusionsOur results demonstrate that sequence divergence, rate heterogeneity and content bias can individually and in combination affect the accuracy with which MCL and UCLUST can recover homologous protein families. For application to data that are more divergent, and exhibit higher among-site rate variation and/or content bias, MCL may often be the better choice, especially if computational resources are not limiting.
| S-EPMC3637521 | biostudies-literature
Project description:Enzymes are governed by unique evolutionary design principles as their catalytic sites were shown to induce long-range evolutionary conservation gradients. We have recently used a comparative bioinformatics approach to disentangle structural determinants from other possible determinants of the evolutionary conservation gradients. The approach is based on comparing the evolutionary patterns of enzymes to those of pseudoenzymes with the same tertiary structure where the catalytic functionality is turned off. This approach provides a way to evaluate several hypotheses regarding the origin of the observed evolutionary conservation gradient in enzymes. The conclusions from such comparative analyses are important for a better understanding of the unique evolutionary design principles of enzymes, which can in turn potentially guide the design of new and improved enzymes.
| S-EPMC6572901 | biostudies-literature
Project description:A major shortcoming of current models of ideological prejudice is that although they can anticipate the direction of the association between participants' ideology and their prejudice against a range of target groups, they cannot predict the size of this association. I developed and tested models that can make specific size predictions for this association. A quantitative model that used the perceived ideology of the target group as the primary predictor of the ideology-prejudice relationship was developed with a representative sample of Americans ( N = 4,940) and tested against models using the perceived status of and choice to belong to the target group as predictors. In four studies (total N = 2,093), ideology-prejudice associations were estimated, and these observed estimates were compared with the models' predictions. The model that was based only on perceived ideology was the most parsimonious with the smallest errors.
| S-EPMC5466142 | biostudies-literature
Project description:Nuclear receptors are transcription factors that regulate gene expression through the ligand-controlled recruitment of a diverse group of proteins known as coregulators. Most nuclear receptor coregulators function in large multi-protein complexes that modify chromatin and thereby regulate the transcription of target genes. Structural and functional studies are beginning to reveal how these complexes are assembled bringing together multiple functionalities that mediate: recruitment to specific genomic loci through interaction with transcription factors; recruitment of enzymatic activities that either modify or remodel chromatin and targeting the complexes to their chromatin substrate. These activities are regulated by post-translational modifications, alternative splicing and small signalling molecules. This review focuses on our current understanding of coregulator complexes and aims to highlight the common principles that are beginning to emerge.
| S-EPMC3963257 | biostudies-literature
Project description:The sequences of proteins encoded by a genome evolve at different rates. A correlate of a protein's evolutionary rate is its expression level: highly expressed proteins tend to evolve slowly. Some explanations of rate variation and the correlation between rate and expression predict that more slowly evolving and more highly expressed proteins have more favorable equilibrium constants for folding. Proteins from thermophiles generally have more stable folds than proteins from mesophiles, and it is known that there are systematic differences in amino acid content between thermophilic and mesophilic proteins. I examined whether there are analogous correlations of amino acid frequencies with evolutionary rate and expression level within genomes. In most of the organisms analyzed, there is a striking tendency for more slowly evolving proteins to be more thermophile-like in their amino acid compositions when adjustments are made for variation in GC content. More highly expressed proteins also tend to be more thermophile-like by the same criteria. These results suggest that part of the evolutionary rate variation among proteins is due to variation in the strength of selection for stability of the folded state. They also suggest that increasing strength of this selective force with expression level plays a role in the correlation between evolutionary rate and expression level.
| S-EPMC2822289 | biostudies-literature
Project description:The physiological and pharmacological role of nucleic acids structures folded into the non canonical G-quadruplex conformation have recently emerged. Their activities are targeted at vital cellular processes including telomere maintenance, regulation of transcription and processing of the pre-messenger or telomeric RNA. In addition, severe conditions like cancer, fragile X syndrome, Bloom syndrome, Werner syndrome and Fanconi anemia J are related to genomic defects that involve G-quadruplex forming sequences. In this connection G-quadruplex recognition and processing by nucleic acid directed proteins and enzymes represents a key event to activate or deactivate physiological or pathological pathways. In this review we examine protein-G-quadruplex recognition in physiologically significant conditions and discuss how to possibly exploit the interactions' selectivity for targeted therapeutic intervention.
| S-EPMC7126356 | biostudies-literature
Project description:The universal protein knowledgebase (UniProtKB) collects and centralises functional information on proteins across a wide range of species. In addition to the functional information added to all protein entries, for enzymes, which represent 20-40% of most proteomes, UniProtKB provides additional information about Enzyme Commission classification, catalytic activity, cofactors, enzyme regulation, kinetics and pathways, all based on critical assessment of published experimental data. Computer-based analysis and structural data are used to enrich the annotation of the sequence through the identification of active sites and binding sites. While the annotation of enzymes is well-defined, the curation of pseudoenzymes in UniProtKB has highlighted some challenges: how to identify them, how to assess their lack of catalytic activity, how to annotate their lack of catalytic activity in a consistent way and how much can be inferred and propagated from experimental data obtained from other species. Through various examples, we illustrate some of these issues and discuss some of the changes we propose to enhance the annotation and discovery of pseudoenzymes. Ultimately, improving the curation of pseudoenzymes will provide the scientific community with a comprehensive resource for pseudoenzymes, which in turn will lead to a better understanding of the evolution of these molecules, the aetiology of related diseases and the development of drugs.
| S-EPMC7160037 | biostudies-literature
Project description:Pathogens use a variety of secreted and surface proteins to interact with and manipulate their hosts, but a systematic approach for identifying such proteins has been lacking. To identify these 'host-exposed' proteins, we used spatially restricted enzymatic tagging followed by mass spectrometry analysis of Caenorhabditis elegans infected with two species of Nematocida microsporidia. We identified 82 microsporidia proteins inside of intestinal cells, including several pathogen proteins in the nucleus. These microsporidia proteins are enriched in targeting signals, are rapidly evolving and belong to large Nematocida-specific gene families. We also find that large, species-specific families are common throughout microsporidia species. Our data suggest that the use of a large number of rapidly evolving species-specific proteins represents a common strategy for microsporidia to interact with their hosts. The unbiased method described here for identifying potential pathogen effectors represents a powerful approach to study a broad range of pathogens.
| S-EPMC5423893 | biostudies-literature