Selective deployment of transcription factor paralogs with submaximal strength facilitates gene regulation in the immune system.

In multicellular organisms, duplicated genes can diverge through tissue-specific gene expression patterns, as exemplified by highly regulated expression of RUNX transcription factor paralogs with apparent functional redundancy. Here we asked what cell-type-specific biologies might be supported by the selective expression of RUNX paralogs during Langerhans cell and inducible regulatory T cell differentiation. We uncovered functional nonequivalence between RUNX paralogs.

Conserved phosphorylation hotspots in eukaryotic protein domain families.

Protein phosphorylation is the best characterized post-translational modification that regulates almost all cellular processes through diverse mechanisms such as changing protein conformations, interactions, and localization. While the inventory for phosphorylation sites across different species has rapidly expanded, their functional role remains poorly investigated. Here, we combine 537,321 phosphosites from 40 eukaryotic species to identify highly conserved phosphorylation hotspot regions within domain families.

iProteinDB: An Integrative Database of Post-translational Modifications.

Post-translational modification (PTM) serves as a regulatory mechanism for protein function, influencing their stability, interactions, activity and localization, and is critical in many signaling pathways. The best characterized PTM is phosphorylation, whereby a phosphate is added to an acceptor residue, most commonly serine, threonine and tyrosine in metazoans. As proteins are often phosphorylated at multiple sites, identifying those sites that are important for function is a challenging problem.

Absence of Selection for Quantum Coherence in the Fenna-Matthews-Olson Complex: A Combined Evolutionary and Excitonic Study.

We present a study on the evolution of the Fenna-Matthews-Olson bacterial photosynthetic pigment-protein complex. This protein complex functions as an antenna. It transports absorbed photons-excitons-to a reaction center where photosynthetic reactions initiate.

Correction to 'Evolutionary diversification of retinoic acid receptor ligand-binding pocket structure by molecular tinkering'.

[This corrects the article DOI: 10.1098/rsos.150484.

Evolution of protein phosphorylation across 18 fungal species.

Living organisms have evolved protein phosphorylation, a rapid and versatile mechanism that drives signaling and regulates protein function. We report the phosphoproteomes of 18 fungal species and a phylogenetic-based approach to study phosphosite evolution. We observe rapid divergence, with only a small fraction of phosphosites conserved over hundreds of millions of years.

Evolutionary diversification of retinoic acid receptor ligand-binding pocket structure by molecular tinkering.

Whole genome duplications (WGDs) have been classically associated with the origin of evolutionary novelties and the so-called duplication-degeneration-complementation model describes the possible fates of genes after duplication. However, how sequence divergence effectively allows functional changes between gene duplicates is still unclear. In the vertebrate lineage, two rounds of WGDs took place, giving rise to paralogous gene copies observed for many gene families.

Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited.

Transcription and translation require a high concentration of potassium across the entire tree of life. The conservation of a high intracellular potassium was an absolute requirement for the evolution of life on Earth. This was achieved by the interplay of P- and V-ATPases that can set up electrochemical gradients across the cell membrane, an energetically costly process requiring the synthesis of ATP by F-ATPases.

Origin of the response to adrenal and sex steroids: Roles of promiscuity and co-evolution of enzymes and steroid receptors.

Many responses to adrenal and sex steroids are mediated by receptors that belong to the nuclear receptor family of transcription factors. We investigated the co-evolution of these vertebrate steroid receptors and the enzymes that synthesize adrenal and sex steroids through data mining of genomes from cephalochordates [amphioxus], cyclostomes [lampreys, hagfish], chondrichthyes [sharks, rays, skates], actinopterygii [ray-finned fish], sarcopterygii [coelacanths, lungfishes and terrestrial vertebrates]. An ancestor of the estrogen receptor and 3-ketosteroid receptors evolved in amphioxus.

CATH: comprehensive structural and functional annotations for genome sequences.

The latest version of the CATH-Gene3D protein structure classification database (4.0, http://www.cathdb.

Understanding the functional difference between growth arrest-specific protein 6 and protein S: an evolutionary approach.

Although protein S (PROS1) and growth arrest-specific protein 6 (GAS6) proteins are homologous with a high degree of structural similarity, they are functionally different. The objectives of this study were to identify the evolutionary origins from which these functional differences arose. Bioinformatics methods were used to estimate the evolutionary divergence time and to detect the amino acid residues under functional divergence between GAS6 and PROS1.

Positive selection during the evolution of the blood coagulation factors in the context of their disease-causing mutations.

Blood coagulation occurs through a cascade of enzymes and cofactors that produces a fibrin clot, while otherwise maintaining hemostasis. The 11 human coagulation factors (FG, FII-FXIII) have been identified across all vertebrates, suggesting that they emerged with the first vertebrates around 500 Ma. Human FVIII, FIX, and FXI are associated with thousands of disease-causing mutations.

Stability-activity tradeoffs constrain the adaptive evolution of RubisCO.

A well-known case of evolutionary adaptation is that of ribulose-1,5-bisphosphate carboxylase (RubisCO), the enzyme responsible for fixation of CO2 during photosynthesis. Although the majority of plants use the ancestral C3 photosynthetic pathway, many flowering plants have evolved a derived pathway named C4 photosynthesis. The latter concentrates CO2, and C4 RubisCOs consequently have lower specificity for, and faster turnover of, CO2.

Gene3D: Multi-domain annotations for protein sequence and comparative genome analysis.

Gene3D (http://gene3d.biochem.ucl.

Selectome update: quality control and computational improvements to a database of positive selection.

Selectome (http://selectome.unil.ch/) is a database of positive selection, based on a branch-site likelihood test.

Vitellogenin underwent subfunctionalization to acquire caste and behavioral specific expression in the harvester ant Pogonomyrmex barbatus.

The reproductive ground plan hypothesis (RGPH) proposes that the physiological pathways regulating reproduction were co-opted to regulate worker division of labor. Support for this hypothesis in honeybees is provided by studies demonstrating that the reproductive potential of workers, assessed by the levels of vitellogenin (Vg), is linked to task performance. Interestingly, contrary to honeybees that have a single Vg ortholog and potentially fertile nurses, the genome of the harvester ant Pogonomyrmex barbatus harbors two Vg genes (Pb_Vg1 and Pb_Vg2) and nurses produce infertile trophic eggs.

Residue mutations and their impact on protein structure and function: detecting beneficial and pathogenic changes.

The present review focuses on the evolution of proteins and the impact of amino acid mutations on function from a structural perspective. Proteins evolve under the law of natural selection and undergo alternating periods of conservative evolution and of relatively rapid change. The likelihood of mutations being fixed in the genome depends on various factors, such as the fitness of the phenotype or the position of the residues in the three-dimensional structure.

New functional families (FunFams) in CATH to improve the mapping of conserved functional sites to 3D structures.

CATH version 3.5 (Class, Architecture, Topology, Homology, available at http://www.cathdb.

Resolving the ortholog conjecture: orthologs tend to be weakly, but significantly, more similar in function than paralogs.

The function of most proteins is not determined experimentally, but is extrapolated from homologs. According to the "ortholog conjecture", or standard model of phylogenomics, protein function changes rapidly after duplication, leading to paralogs with different functions, while orthologs retain the ancestral function. We report here that a comparison of experimentally supported functional annotations among homologs from 13 genomes mostly supports this model.

Evolution of the epithelial sodium channel and the sodium pump as limiting factors of aldosterone action on sodium transport.

Despite large changes in salt intake, the mammalian kidney is able to maintain the extracellular sodium concentration and osmolarity within very narrow margins, thereby controlling blood volume and blood pressure. In the aldosterone-sensitive distal nephron (ASDN), aldosterone tightly controls the activities of epithelial sodium channel (ENaC) and Na,K-ATPase, the two limiting factors in establishing transepithelial sodium transport. It has been proposed that the ENaC/degenerin gene family is restricted to Metazoans, whereas the α- and β-subunits of Na,K-ATPase have homologous genes in prokaryotes.

Large-scale analysis of orthologs and paralogs under covarion-like and constant-but-different models of amino acid evolution.

Functional divergence between homologous proteins is expected to affect amino acid sequences in two main ways, which can be considered as proxies of biochemical divergence: a "covarion-like" pattern of correlated changes in evolutionary rates, and switches in conserved residues ("conserved but different"). Although these patterns have been used in case studies, a large-scale analysis is needed to estimate their frequency and distribution. We use a phylogenomic framework of animal genes to answer three questions: 1) What is the prevalence of such patterns? 2) Can we link such patterns at the amino acid level with selection inferred at the codon level? 3) Are patterns different between paralogs and orthologs? We find that covarion-like patterns are more frequently detected than "constant but different," but that only the latter are correlated with signal for positive selection.

Adaptive divergence of ancient gene duplicates in the avian MHC class II beta.

Gene duplication and neofunctionalization are known to be important processes in the evolution of phenotypic complexity. They account for important evolutionary novelties that confer ecological adaptation, such as the major histocompatibility complex (MHC), a multigene family crucial to the vertebrate immune system. In birds, two MHC class II β (MHCIIβ) exon 3 lineages have been recently characterized, and two hypotheses for the evolutionary history of MHCIIβ lineages were proposed.

Evidence for an episodic model of protein sequence evolution.

The evolution of protein function appears to involve alternating periods of conservative evolution and of relatively rapid change. Evidence for such episodic evolution, consistent with some theoretical expectations, comes from the application of increasingly sophisticated models of evolution to large sequence datasets. We present here some of the recent methods to detect functional shifts, using amino acid or codon models.

How confident can we be that orthologs are similar, but paralogs differ?

Homologous genes are classified into orthologs and paralogs, depending on whether they arose by speciation or duplication. It is widely assumed that orthologs share similar functions, whereas paralogs are expected to diverge more from each other. But does this assumption hold up on further examination? We present evidence that orthologs and paralogs are not so different in either their evolutionary rates or their mechanisms of divergence.

Structural and evolutionary innovation of the heterodimerization interface between USP and the ecdysone receptor ECR in insects.

Understanding how the variability of protein structure arises during evolution and leads to new structure-function relationships ultimately promoting evolutionary novelties is a major goal of molecular evolution and is critical for interpreting genome sequences. We addressed this issue using the ecdysone receptor (ECR), a major developmental factor that controls development and reproduction of arthropods. The functional ECR is a heterodimer of two nuclear receptors: ECR, which binds ecdysteroids, and its obligatory partner ultraspirade (USP), which is orthologous to the retinoid X receptor of vertebrates.