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A unified structural model of the mammalian translocator protein (TSPO).
Xia Y, Ledwitch K, Kuenze G, Duran A, Li J, Sanders CR, Manning C, Meiler J
(2019) J Biomol NMR 73: 347-364
MeSH Terms: Animals, Bacterial Proteins, Ligands, Mammals, Mice, Mitochondrial Membrane Transport Proteins, Models, Molecular, Molecular Imaging, Nuclear Magnetic Resonance, Biomolecular, Protein Binding, Protein Conformation, Receptors, GABA
Show Abstract · Added March 21, 2020
The translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), is a membrane protein located on the outer mitochondrial membrane. Experimentally-derived structures of mouse TSPO (mTSPO) and its homologs from bacterial species have been determined by NMR spectroscopy and X-ray crystallography, respectively. These structures and ligand interactions within the TSPO binding pocket display distinct differences. Here, we leverage experimental and computational studies to derive a unified structural model of mTSPO in the presence and absence of the TSPO ligand, PK11195, and study the effects of DPC detergent micelles on the TSPO structure and ligand binding. From this work, we conclude that that the lipid-mimetic system used to solubilize mTSPO for NMR studies thermodynamically destabilizes the protein, introduces structural perturbations, and alters the characteristics of ligand binding. Furthermore, we used Rosetta to construct a unified mTSPO model that reconciles deviating features of the mammalian and bacterial TSPO. These deviating features are likely a consequence of the detergent system used for structure determination of mTSPO by NMR. The unified mTSPO model agrees with available experimental NMR data, appears to be physically realistic (i.e. thermodynamically not frustrated as judged by the Rosetta energy function), and simultaneously shares the structural features observed in sequence-conserved regions of the bacterial proteins. Finally, we identified the binding site for an imaging ligand VUIIS8310 that is currently positioned for clinical translation using NMR spectroscopy and propose a computational model of the VUIIS8310-mTSPO complex.
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Arrestin mutations: Some cause diseases, others promise cure.
Gurevich VV, Gurevich EV
(2019) Prog Mol Biol Transl Sci 161: 29-45
MeSH Terms: Animals, Arrestin, Disease, Eye, Humans, Mammals, Models, Biological, Mutation
Show Abstract · Added March 18, 2020
Arrestins play a key role in homologous desensitization of G protein-coupled receptors (GPCRs) and regulate several other vital signaling pathways in cells. Considering the critical roles of these proteins in cellular signaling, surprisingly few disease-causing mutations in human arrestins were described. Most of these are loss-of-function mutations of visual arrestin-1 that cause excessive rhodopsin signaling and hence night blindness. Only one dominant arrestin-1 mutation was discovered so far. It reduces the thermal stability of the protein, which likely results in photoreceptor death via unfolded protein response. In case of the two nonvisual arrestins, only polymorphisms were described, some of which appear to be associated with neurological disorders and altered response to certain treatments. Structure-function studies revealed several ways of enhancing arrestins' ability to quench GPCR signaling. These enhanced arrestins have potential as tools for gene therapy of disorders associated with excessive signaling of mutant GPCRs.
© 2019 Elsevier Inc. All rights reserved.
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Use of chemical probes to explore the toxicological potential of the K/Cl cotransporter (KCC) as a novel insecticide target to control the primary vector of dengue and Zika virus, Aedes aegypti.
Prael FJ, Chen R, Li Z, Reed CW, Lindsley CW, Weaver CD, Swale DR
(2018) Pestic Biochem Physiol 151: 10-17
MeSH Terms: Aedes, Animals, Dengue, Drosophila, Insecticides, Mammals, Mosquito Vectors, Nervous System, Symporters, Zika Virus
Show Abstract · Added April 10, 2019
The majority of commercialized insecticides target the insect nervous system and therefore, neural proteins are well-validated targets for insecticide development. Considering that only a few neural targets are exploited for insecticidal action and the development of insecticide resistance has reduced the efficacy of current insecticidal classes, we sought to test the toxicological potential of the potassium-chloride cotransporter (KCC). In mammals, KCC proteins have seminal roles in shaping GABAergic signaling and inhibitory neurotransmission, thus ion transport through KCC is critical for proper neurotransmission. Therefore, we hypothesized that mosquito KCC represents a putative insecticide target site and that pharmacological inhibition of KCC constructs in Aedes aegypti will be lethal. To test this hypothesis, we developed a robust, cell-based fluorescence assay that enables in vitro characterization of small-molecules against Ae. aegypti KCC and performed a proof-of-concept study employing well characterized mammalian KCC modulators to determine the toxicological potential of Ae. aegypti KCC. The selective inhibitor of mammalian KCC, termed VU0463271, was found to be a potent inhibitor Ae. aegypti KCC and microinjection induced lethality in a concentration-dependent manner to susceptible and pyrethroid resistant strains. Importantly, an analog of VU0463271 was shown to be >40-fold less potent and did not induce toxicity, suggesting that the observed physiological effects and mortality are likely due to KCC inhibition. This proof-of-concept study suggests that Ae. aegypti KCC represents a putative target site for mosquitocide design that can mitigate the current mechanisms of insecticide resistance.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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Prediction of gene regulatory enhancers across species reveals evolutionarily conserved sequence properties.
Chen L, Fish AE, Capra JA
(2018) PLoS Comput Biol 14: e1006484
MeSH Terms: Animals, Conserved Sequence, Enhancer Elements, Genetic, Evolution, Molecular, Genomics, Humans, Machine Learning, Mammals, Neural Networks, Computer, Sequence Alignment, Sequence Analysis, DNA, Support Vector Machine
Show Abstract · Added March 3, 2020
Genomic regions with gene regulatory enhancer activity turnover rapidly across mammals. In contrast, gene expression patterns and transcription factor binding preferences are largely conserved between mammalian species. Based on this conservation, we hypothesized that enhancers active in different mammals would exhibit conserved sequence patterns in spite of their different genomic locations. To investigate this hypothesis, we evaluated the extent to which sequence patterns that are predictive of enhancers in one species are predictive of enhancers in other mammalian species by training and testing two types of machine learning models. We trained support vector machine (SVM) and convolutional neural network (CNN) classifiers to distinguish enhancers defined by histone marks from the genomic background based on DNA sequence patterns in human, macaque, mouse, dog, cow, and opossum. The classifiers accurately identified many adult liver, developing limb, and developing brain enhancers, and the CNNs outperformed the SVMs. Furthermore, classifiers trained in one species and tested in another performed nearly as well as classifiers trained and tested on the same species. We observed similar cross-species conservation when applying the models to human and mouse enhancers validated in transgenic assays. This indicates that many short sequence patterns predictive of enhancers are largely conserved. The sequence patterns most predictive of enhancers in each species matched the binding motifs for a common set of TFs enriched for expression in relevant tissues, supporting the biological relevance of the learned features. Thus, despite the rapid change of active enhancer locations between mammals, cross-species enhancer prediction is often possible. Our results suggest that short sequence patterns encoding enhancer activity have been maintained across more than 180 million years of mammalian evolution.
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What is a placental mammal anyway?
Abbot P, Capra JA
(2017) Elife 6:
MeSH Terms: Animals, Eutheria, Evolution, Molecular, Female, Gene Expression Regulation, Developmental, Humans, Lactation, Mammals, Mammary Glands, Human, Marsupialia, Placentation, Pregnancy
Show Abstract · Added March 14, 2018
Many developmental functions in marsupials and eutherian mammals are accomplished by different tissues, but similar genes.
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12 MeSH Terms
Mammalian pregnancy.
Abbot P, Rokas A
(2017) Curr Biol 27: R127-R128
MeSH Terms: Animals, Female, Mammals, Pregnancy
Show Abstract · Added April 6, 2017
Patrick Abbot & Antonis Rokas introduce the biology of pregnancy in mammals.
Copyright © 2017 Elsevier Ltd. All rights reserved.
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4 MeSH Terms
The mammal-specific Pdx1 Area II enhancer has multiple essential functions in early endocrine cell specification and postnatal β-cell maturation.
Yang YP, Magnuson MA, Stein R, Wright CV
(2017) Development 144: 248-257
MeSH Terms: Animals, Binding Sites, Cell Differentiation, Embryo, Mammalian, Enhancer Elements, Genetic, Gene Expression Regulation, Developmental, Homeodomain Proteins, Insulin-Secreting Cells, Islets of Langerhans, Mammals, Mice, Mice, Transgenic, Organogenesis, Species Specificity, Trans-Activators
Show Abstract · Added December 29, 2016
The transcription factor Pdx1 is required for multiple aspects of pancreatic organogenesis. It remains unclear to what extent Pdx1 expression and function depend upon trans-activation through 5' conserved cis-regulatory regions and, in particular, whether the mammal-specific Area II (-2139 to -1958 bp) affects minor or major aspects of organogenesis. We show that Area II is a primary effector of endocrine-selective transcription in epithelial multipotent cells, nascent endocrine progenitors, and differentiating and mature β cells in vivo Pdx1 mice exhibit a massive reduction in endocrine progenitor cells and progeny hormone-producing cells, indicating that Area II activity is fundamental to mounting an effective endocrine lineage-specification program within the multipotent cell population. Creating an Area II-deleted state within already specified Neurog3-expressing endocrine progenitor cells increased the proportion of glucagon α relative to insulin β cells, associated with the transcriptional and epigenetic derepression of the α-cell-determining Arx gene in endocrine progenitors. There were also glucagon and insulin co-expressing cells, and β cells that were incapable of maturation. Creating the Pdx1 state after cells entered an insulin-expressing stage led to immature and dysfunctional islet β cells carrying abnormal chromatin marking in vital β-cell-associated genes. Therefore, trans-regulatory integration through Area II mediates a surprisingly extensive range of progenitor and β-cell-specific Pdx1 functions.
© 2017. Published by The Company of Biologists Ltd.
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15 MeSH Terms
A Genome-Scale Investigation of How Sequence, Function, and Tree-Based Gene Properties Influence Phylogenetic Inference.
Shen XX, Salichos L, Rokas A
(2016) Genome Biol Evol 8: 2565-80
MeSH Terms: Animals, Base Composition, Genome, Fungal, Mammals, Phylogeny, Sequence Alignment, Yeasts
Show Abstract · Added April 6, 2017
Molecular phylogenetic inference is inherently dependent on choices in both methodology and data. Many insightful studies have shown how choices in methodology, such as the model of sequence evolution or optimality criterion used, can strongly influence inference. In contrast, much less is known about the impact of choices in the properties of the data, typically genes, on phylogenetic inference. We investigated the relationships between 52 gene properties (24 sequence-based, 19 function-based, and 9 tree-based) with each other and with three measures of phylogenetic signal in two assembled data sets of 2,832 yeast and 2,002 mammalian genes. We found that most gene properties, such as evolutionary rate (measured through the percent average of pairwise identity across taxa) and total tree length, were highly correlated with each other. Similarly, several gene properties, such as gene alignment length, Guanine-Cytosine content, and the proportion of tree distance on internal branches divided by relative composition variability (treeness/RCV), were strongly correlated with phylogenetic signal. Analysis of partial correlations between gene properties and phylogenetic signal in which gene evolutionary rate and alignment length were simultaneously controlled, showed similar patterns of correlations, albeit weaker in strength. Examination of the relative importance of each gene property on phylogenetic signal identified gene alignment length, alongside with number of parsimony-informative sites and variable sites, as the most important predictors. Interestingly, the subsets of gene properties that optimally predicted phylogenetic signal differed considerably across our three phylogenetic measures and two data sets; however, gene alignment length and RCV were consistently included as predictors of all three phylogenetic measures in both yeasts and mammals. These results suggest that a handful of sequence-based gene properties are reliable predictors of phylogenetic signal and could be useful in guiding the choice of phylogenetic markers.
© The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
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7 MeSH Terms
Evolution of lysine acetylation in the RNA polymerase II C-terminal domain.
Simonti CN, Pollard KS, Schröder S, He D, Bruneau BG, Ott M, Capra JA
(2015) BMC Evol Biol 15: 35
MeSH Terms: Acetylation, Animals, Cell Adhesion, Cell Growth Processes, Evolution, Molecular, Gene Expression Regulation, Humans, Lysine, Mammals, Promoter Regions, Genetic, Protein Structure, Tertiary, RNA Polymerase II, Vertebrates
Show Abstract · Added February 22, 2016
BACKGROUND - RPB1, the largest subunit of RNA polymerase II, contains a highly modifiable C-terminal domain (CTD) that consists of variations of a consensus heptad repeat sequence (Y1S2P3T4S5P6S7). The consensus CTD repeat motif and tandem organization represent the ancestral state of eukaryotic RPB1, but across eukaryotes CTDs show considerable diversity in repeat organization and sequence content. These differences may reflect lineage-specific CTD functions mediated by protein interactions. Mammalian CTDs contain eight non-consensus repeats with a lysine in the seventh position (K7). Posttranslational acetylation of these sites was recently shown to be required for proper polymerase pausing and regulation of two growth factor-regulated genes.
RESULTS - To investigate the origins and function of RPB1 CTD acetylation (acRPB1), we computationally reconstructed the evolution of the CTD repeat sequence across eukaryotes and analyzed the evolution and function of genes dysregulated when acRPB1 is disrupted. Modeling the evolutionary dynamics of CTD repeat count and sequence content across diverse eukaryotes revealed an expansion of the CTD in the ancestors of Metazoa. The new CTD repeats introduced the potential for acRPB1 due to the appearance of distal repeats with lysine at position seven. This was followed by a further increase in the number of lysine-containing repeats in developmentally complex clades like Deuterostomia. Mouse genes enriched for acRPB1 occupancy at their promoters and genes with significant expression changes when acRPB1 is disrupted are enriched for several functions, such as growth factor response, gene regulation, cellular adhesion, and vascular development. Genes occupied and regulated by acRPB1 show significant enrichment for evolutionary origins in the early history of eukaryotes through early vertebrates.
CONCLUSIONS - Our combined functional and evolutionary analyses show that RPB1 CTD acetylation was possible in the early history of animals, and that the K7 content of the CTD expanded in specific developmentally complex metazoan lineages. The functional analysis of genes regulated by acRPB1 highlight functions involved in the origin of and diversification of complex Metazoa. This suggests that acRPB1 may have played a role in the success of animals.
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13 MeSH Terms
Symmetry breakage in the vertebrate embryo: when does it happen and how does it work?
Blum M, Schweickert A, Vick P, Wright CV, Danilchik MV
(2014) Dev Biol 393: 109-23
MeSH Terms: Animals, Body Patterning, Embryo, Mammalian, Embryo, Nonmammalian, Fishes, Gene Expression Regulation, Developmental, H(+)-K(+)-Exchanging ATPase, Left-Right Determination Factors, Mammals, Mesoderm, Nodal Protein, Organizers, Embryonic, Serotonin, Signal Transduction, Vertebrates, Xenopus
Show Abstract · Added December 3, 2014
Asymmetric development of the vertebrate embryo has fascinated embryologists for over a century. Much has been learned since the asymmetric Nodal signaling cascade in the left lateral plate mesoderm was detected, and began to be unraveled over the past decade or two. When and how symmetry is initially broken, however, has remained a matter of debate. Two essentially mutually exclusive models prevail. Cilia-driven leftward flow of extracellular fluids occurs in mammalian, fish and amphibian embryos. A great deal of experimental evidence indicates that this flow is indeed required for symmetry breaking. An alternative model has argued, however, that flow simply acts as an amplification step for early asymmetric cues generated by ion flux during the first cleavage divisions. In this review we critically evaluate the experimental basis of both models. Although a number of open questions persist, the available evidence is best compatible with flow-based symmetry breakage as the archetypical mode of symmetry breakage.
Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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16 MeSH Terms