Mitochondrial targeting adaptation of the hominoid-specific glutamate dehydrogenase driven by positive Darwinian selection

Many new gene copies emerged by gene duplication in hominoids, but little is known with respect to their functional evolution. Glutamate dehydrogenase (GLUD) is an enzyme central to the glutamate and energy metabolism of the cell. In addition to the single, GLUD-encoding gene present in all mammals (GLUD1), humans and apes acquired a second GLUD gene (GLUD2) through retroduplication of GLUD1, which codes for an enzyme with unique, potentially brain-adapted properties. Here we show that whereas the GLUD1 parental protein localizes to mitochondria and the cytoplasm, GLUD2 is specifically targeted to mitochondria. Using evolutionary analysis and resurrected ancestral protein variants, we demonstrate that the enhanced mitochondrial targeting specificity of GLUD2 is due to a single positively selected glutamic acid-to-lysine substitution, which was fixed in the N-terminal mitochondrial targeting sequence (MTS) of GLUD2 soon after the duplication event in the hominoid ancestor ~18–25 million years ago. This MTS substitution arose in parallel with two crucial adaptive amino acid changes in the enzyme and likely contributed to the functional adaptation of GLUD2 to the glutamate metabolism of the hominoid brain and other tissues. We suggest that rapid, selectively driven subcellular adaptation, as exemplified by GLUD2, represents a common route underlying the emergence of new gene functions

PhyloPattern: regular expressions to identify complex patterns in phylogenetic trees

<p>Abstract</p> <p>Background</p> <p>To effectively apply evolutionary concepts in genome-scale studies, large numbers of phylogenetic trees have to be automatically analysed, at a level approaching human expertise. Complex architectures must be recognized within the trees, so that associated information can be extracted.</p> <p>Results</p> <p>Here, we present a new software library, PhyloPattern, for automating tree manipulations and analysis. PhyloPattern includes three main modules, which address essential tasks in high-throughput phylogenetic tree analysis: node annotation, pattern matching, and tree comparison. PhyloPattern thus allows the programmer to focus on: i) the use of predefined or user defined annotation functions to perform immediate or deferred evaluation of node properties, ii) the search for user-defined patterns in large phylogenetic trees, iii) the pairwise comparison of trees by dynamically generating patterns from one tree and applying them to the other.</p> <p>Conclusion</p> <p>PhyloPattern greatly simplifies and accelerates the work of the computer scientist in the evolutionary biology field. The library has been used to automatically identify phylogenetic evidence for domain shuffling or gene loss events in the evolutionary histories of protein sequences. However any workflow that relies on phylogenetic tree analysis, could be automated with PhyloPattern.</p

TBC1D3, a Hominoid-Specific Gene, Delays IRS-1 Degradation and Promotes Insulin Signaling by Modulating p70 S6 Kinase Activity

Insulin/IGF-1 signaling plays a pivotal role in the regulation of cellular homeostasis through its control of glucose metabolism as well as due to its effects on cell proliferation. Aberrant regulation of insulin signaling has been repeatedly implicated in uncontrolled cell growth and malignant transformations. TBC1D3 is a hominoid specific gene previously identified as an oncogene in breast and prostate cancers. Our efforts to identify the molecular mechanisms of TBC1D3-induced oncogenesis revealed the role of TBC1D3 in insulin/IGF-1 signaling pathway. We document here that TBC1D3 intensifies insulin/IGF-1-induced signal transduction through intricate, yet elegant fine-tuning of signaling mechanisms. We show that TBC1D3 expression substantially delayed ubiquitination and degradation of insulin receptor substrate-1 (IRS-1). This effect is achieved through suppression of serine phosphorylation at S636/639, S307 and S312 of IRS-1, which are key phosphorylation sites required for IRS-1 degradation. Furthermore, we report that the effect of TBC1D3 on IRS-1:S636/639 phosphorylation is mediated through TBC1D3-induced activation of protein phosphatase 2A (PP2A), followed by suppression of T389 phosphorylation on p70 S6 kinase (S6K). TBC1D3 specifically interacts with PP2A regulatory subunit B56γ, indicating that TBC1D3 and PP2A B56γ operate jointly to promote S6K:T389 dephosphorylation. These findings suggest that TBC1D3 plays an unanticipated and potentially unique role in the fine-tuning of insulin/IGF-1 signaling, while providing novel insights into the regulation of tumorigenesis by a hominoid-specific protein

Fusion and Fission of Genes Define a Metric between Fungal Genomes

Gene fusion and fission events are key mechanisms in the evolution of gene architecture, whose effects are visible in protein architecture when they occur in coding sequences. Until now, the detection of fusion and fission events has been performed at the level of protein sequences with a post facto removal of supernumerary links due to paralogy, and often did not include looking for events defined only in single genomes. We propose a method for the detection of these events, defined on groups of paralogs to compensate for the gene redundancy of eukaryotic genomes, and apply it to the proteomes of 12 fungal species. We collected an inventory of 1,680 elementary fusion and fission events. In half the cases, both composite and element genes are found in the same species. Per-species counts of events correlate with the species genome size, suggesting a random mechanism of occurrence. Some biological functions of the genes involved in fusion and fission events are slightly over- or under-represented. As already noted in previous studies, the genes involved in an event tend to belong to the same functional category. We inferred the position of each event in the evolution tree of the 12 fungal species. The event localization counts for all the segments of the tree provide a metric that depicts the “recombinational” phylogeny among fungi. A possible interpretation of this metric as distance in adaptation space is proposed

The ARE-dependent mRNA-destabilizing activity of BRF1 is regulated by protein kinase B

Butyrate response factor (BRF1) belongs to the Tis11 family of CCCH zinc-finger proteins, which bind to mRNAs containing an AU-rich element (ARE) in their 3′ untranslated region and promote their deadenylation and rapid degradation. Independent signal transduction pathways have been reported to stabilize ARE-containing transcripts by a process thought to involve phosphorylation of ARE-binding proteins. Here we report that protein kinase B (PKB/Akt) stabilizes ARE transcripts by phosphorylating BRF1 at serine 92 (S92). Recombinant BRF1 promoted in vitro decay of ARE-containing mRNA (ARE-mRNA), yet phosphorylation by PKB impaired this activity. S92 phosphorylation of BRF1 did not impair ARE binding, but induced complex formation with the scaffold protein 14-3-3. In vivo and in vitro data support a model where PKB causes ARE-mRNA stabilization by inactivating BRF1 through binding to 14-3-3

Identification of an erythroid-enriched endoribonuclease activity involved in specific mRNA cleavage

Stability of the human α–globin mRNA is conferred by a ribonucleoprotein complex termed the α–complex, which acts by impeding deadenylation. Using our recently devised in vitro decay assay, we demonstrate that the α–complex also functions by protecting the 3′–untranslated region (3′-UTR) from an erythroid-enriched, sequence-specific endoribonuclease activity. The cleavage site was mapped to a region protected by the α–complex and is regulated by the presence of the α–complex. Similar endoribonuclease cleavage products were also detected in erythroid cells expressing an exogenous α–globin gene. Nucleotide substitution of the target sequence renders the RNA refractory to the endoribonuclease activity. Insertion of the target sequence onto a heterologous RNA confers sequence-specific cleavage on the chimeric RNA, demonstrating the sequence specificity of this activity. We conclude that the α–complex stabilizes the α–globin mRNA in erythroid cells by a multifaceted approach, one aspect of which is to protect the 3′–UTR from specific endoribonuclease cleavage