Tex19 and Sectm1 concordant molecular phylogenies support co-evolution of both eutherian-specific genes

International audienceBackground: Transposable elements (TE) have attracted much attention since they shape the genome and contribute to species evolution. Organisms have evolved mechanisms to control TE activity. Testis expressed 19 (Tex19) represses TE expression in mouse testis and placenta. In the human and mouse genomes, Tex19 and Secreted and transmembrane 1 (Sectm1) are neighbors but are not homologs. Sectm1 is involved in immunity and its molecular phylogeny is unknown. Methods: Using multiple alignments of complete protein sequences (MACS), we inferred Tex19 and Sectm1 molecular phylogenies. Protein conserved regions were identified and folds were predicted. Finally, expression patterns were studied across tissues and species using RNA-seq public data and RT-PCR. Results: We present 2 high quality alignments of 58 Tex19 and 58 Sectm1 protein sequences from 48 organisms. First, both genes are eutherian-specific, i.e., exclusively present in mammals except monotremes (platypus) and marsupials. Second, Tex19 and Sectm1 have both duplicated in Sciurognathi and Bovidae while they have remained as single copy genes in all further placental mammals. Phylogenetic concordance between both genes was significant (p-value < 0.05) and supported co-evolution and functional relationship. At the protein level, Tex19 exhibits 3 conserved regions and 4 invariant cysteines. In particular, a CXXC motif is present in the N-terminal conserved region. Sectm1 exhibits 2 invariant cysteines and an Ig-like domain. Strikingly, Tex19 C-terminal conserved region was lost in Haplorrhini primates while a Sectm1 C-terminal extra domain was acquired. Finally, we have determined that Tex19 and Sectm1 expression levels anti-correlate across the testis of several primates (ρ = −0.72) which supports anti-regulation. Conclusions: Tex19 and Sectm1 co-evolution and anti-regulated expressions support a strong functional relationship between both genes. Since Tex19 operates a control on TE and Sectm1 plays a role in immunity, Tex19 might suppress an immune response directed against cells that show TE activity in eutherian reproductive tissues

Post-translational modifications in DNA topoisomerase 2α highlight the role of a eukaryote-specific residue in the ATPase domain

Type 2 DNA topoisomerases (Top2) are critical components of key protein complexes involved in DNA replication, chromosome condensation and segregation, as well as gene transcription. The Top2 were found to be the main targets of anticancer agents, leading to intensive efforts to understand their functional and physiological role as well as their molecular structure. Post-translational modifications have been reported to influence Top2 enzyme activities in particular those of the mammalian Top2α isoform. In this study, we identified phosphorylation, and for the first time, acetylation sites in the human Top2α isoform produced in eukaryotic expression systems. Structural analysis revealed that acetylation sites are clustered on the catalytic domains of the homodimer while phosphorylation sites are located in the C-terminal domain responsible for nuclear localization. Biochemical analysis of the eukaryotic-specific K168 residue in the ATPase domain shows that acetylation affects a key position regulating ATP hydrolysis through the modulation of dimerization. Our findings suggest that acetylation of specific sites involved in the allosteric regulation of human Top2 may provide a mechanism for modulation of its catalytic activity.Fil: Bedez, Claire. Université de Strasbourg; FranciaFil: Lotz, Christophe. Université de Strasbourg; FranciaFil: Batisse, Claire. Université de Strasbourg; FranciaFil: Broeck, Arnaud Vanden. Université de Strasbourg; FranciaFil: Stote, Roland H.. Université de Strasbourg; FranciaFil: Howard, Eduardo Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; ArgentinaFil: Pradeau-Aubreton, Karine. Université de Strasbourg; FranciaFil: Ruff, Marc. Université de Strasbourg; FranciaFil: Lamour, Valérie. Université de Strasbourg; Franci

Post-translational modifications in DNA topoisomerase 2α highlight the role of a eukaryote-specific residue in the ATPase domain

Type 2 DNA topoisomerases (Top2) are critical components of key protein complexes involved in DNA replication, chromosome condensation and segregation, as well as gene transcription. The Top2 were found to be the main targets of anticancer agents, leading to intensive efforts to understand their functional and physiological role as well as their molecular structure. Post-translational modifications have been reported to influence Top2 enzyme activities in particular those of the mammalian Top2α isoform. In this study, we identified phosphorylation, and for the first time, acetylation sites in the human Top2α isoform produced in eukaryotic expression systems. Structural analysis revealed that acetylation sites are clustered on the catalytic domains of the homodimer while phosphorylation sites are located in the C-terminal domain responsible for nuclear localization. Biochemical analysis of the eukaryotic-specific K168 residue in the ATPase domain shows that acetylation affects a key position regulating ATP hydrolysis through the modulation of dimerization. Our findings suggest that acetylation of specific sites involved in the allosteric regulation of human Top2 may provide a mechanism for modulation of its catalytic activity.Facultad de Ciencias ExactasInstituto de Física de Líquidos y Sistemas Biológico

GÖÇ VE YAŞAM

Uluslararası Bakalorya Programı, A1 dersi Türk Dili ve Edebiyatı alanında ele alınan bu tezde, Orhan Kemal'in Gurbet Kuşları adlı yapıtında göç olgusu nedenleri ve sonuçlarıyla beraber incelenmiştir. Göç olgusuyla değişen toplumsal yapı, ekonomik ve kültürel farklılıklar çerçevesinde değerlendirilmiştir. Bu tezin amacı, göç olgusunun toplumsal yapıda alt sınıf ve üst sınıflardaki bireyler üzerindeki etkilerini ortaya koymaktır. Üç ana bölümden oluşan tezin ilk bölümünde yapıta adını veren Gurbet Kuşları kavramı üzerinde durulmuştur. Köylülerin aidiyetsizliği ve uyum sorunu bu bölümde aktarılmıştır. Tezin ikinci bölümünde ise köylülerin köyden kente göç sürecinde yaşadıkları kadın ve erkek figürler üzerinden neden ve sonuçlarıyla işlenmiştir. Tezin üçüncü bölümünde şehirliler başlığı altından genel olarak şehirde – İstanbul – yaşayan insanların göç sürecinde köylülerle yaşadıkları uyumsuzluk ve çatışmalara yer verilmektedir. Çalışmada göç sürecinde şehre yerleşen figürlerin şehirlilerle aralarındaki ekonomik ve kültürel farklılıkların sınıflar arasında geçişe olanak tanımadığı sonucuna varılmıştır

1-Hydroxy-2(1H)-pyridinone-Based Chelators with Potential Catechol O-Methyl Transferase Inhibition and Neurorescue Dual Action against Parkinson’s Disease

Two analogues of tolcapone where the nitrocatechol group has been replaced by a 1-hydroxy-2(1H)-pyridinone have been designed and synthesised. These compounds are expected to have a dual mode of action both beneficial against Parkinson’s disease: they are designed to be inhibitors of catechol O-methyl transferase, which contribute to the reduction of dopamine in the brain, and to protect neurons against oxidative damage. To assess whether these compounds are worthy of biological assessment to demonstrate these effects, measurement of their pKa and stability constants for Fe(III), in silico modelling of their potential to inhibit COMT and blood–brain barrier scoring were performed. These results demonstrate that the compounds may indeed have the desired properties, indicating they are indeed promising candidates for further evaluation

Structural basis for hijacking of cellular LxxLL motifs by papillomavirus E6 oncoproteins

E6 viral oncoproteins are key players in epithelial tumors induced by papillomaviruses in vertebrates, including cervical cancer in humans. E6 proteins target many host proteins by specifically interacting with acidic LxxLL motifs. We solved the crystal structures of bovine (BPV1) and human (HPV16) papillomavirus E6 proteins bound to LxxLL peptides from the focal adhesion protein paxillin and the ubiquitin ligase E6AP, respectively. In both E6 proteins, two zinc domains and a linker helix form a basic-hydrophobic pocket, which captures helical LxxLL motifs in a way compatible with other interaction modes. Mutational inactivation of the LxxLL binding pocket disrupts the oncogenic activities of both E6 proteins. This work reveals the structural basis of both the multifunctionality and the oncogenicity of E6 proteins

Theoretical investigations of vibrational energy relaxation in solution

A rigorous theoretical treatment of vibrational energy relaxation in solution has been developed based on a general theory of dynamics of chemical reactions in solution. Algorithms which permit the construction of a physically realistic generalized Langevin equation of motion for the energy relaxation dynamics of a specified normal mode coordinate immersed at infinite dilution in monatomic and molecular solvent are developed. These algorithms permit the construction, from equilibrium solute-solvent pair correlation functions, of the liquid state frequency of the normal mode, \omega\sb{l}, and of the Gaussian model approximation to the autocorrelation function \langle\tilde{\cal F}(t)\tilde{\cal F}\rangle\sb{o} of the fluctuating force exerted by the solvent on the solute normal mode. From these quantities, one may compute the vibration energy relaxation time T\sb1 of the solute normal mode and assess the relative importance of the various energy dissipation pathways, solute vibration $\leftrightarrow$ solvent, solute vibration $\leftrightarrow$ solute translation $\leftrightarrow$ solvent, and solute vibration $\leftrightarrow$ solute translation, solute rotation $\leftrightarrow$ solvent. Numerical studies are presented for the prototype case of a diatomic solute in a monatomic solvent along with studies of more chemically interesting systems in molecular solvents. The study of VER in neat O\sb2 is presented

Etude théorique de la protéine de nucléocapside NCp7 du VIH-1

STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Etude in silico de l'allostérie et des changements conformationnels de grande envergure dans les intégrines

Les intégrines sont des protéines transmembranaires qui jouent un rôle primordial dans l'adhésion cellulaire. Des études expérimentales ont montré qu'elles se comportaient comme des commutateurs bidirectionnels allostériques et subissaient de grands changements conformationnels. L'objectif de ce travail est d'analyser les changements de conformation qui accompagnent le fonctionnement des intégrines par la modélisation moléculaire. De multiples structures du I-domaine ont tout d'abord été soumises à une analyse comparative en modes normaux. La dynamique des domaines I-like et Hybrid a ensuite été étudiée par une analyse quasi-harmonique. Enfin, l'activation de la partie extracellulaire complète de l'intégrine a été étudiée par dynamique moléculaire ciblée.Le travail réalisé apporte un point de vue nouveau sur la dynamique des intégrines et permet d'améliorer la connaissance des mécanismes moléculaires réalisant le couplage entre la conformation et l'affinité pour les ligands.Integrins are transmembrane proteins playing a central role in cellular adhesion. Experimental studies have shown that they behave as bidirectional allosteric transmitters and were subjected to large-scale conformational changes. The aim of this work is to analyse by molecular modelling the conformational changes associated with integrin function. Multiple structures of the I-domain have first been submitted to a comparative normal mode analysis. Dynamics of the I-like and Hybrid domain has then been studied by quasi-harmonic analysis. At last, activation of the complete extracellular part of the integrin has been studied by targeted molecular dynamics. This work brings a new point of view on integrin dynamics and contributes to improve our knowledge of the molecular mechanisms involved in the coupling between the conformation and the affinity for ligands.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Effects of loop conformation on pKa and ligand binding in DNA gyrase B

Molecular dynamics simulations of the adenosine triphosphatase (ATPase) subdomain of DNA gyrase B were done to characterize the flexibility of two loops implicated in ligand binding. The simulations show that bound adenosine triphosphate (ATP) stabilizes the conformation of the two loops. Simulations of the ATPase subdomain without ATP show that the loops are more flexible and can assume alternative conformations. We further investigated the dependence of histidine pKa on the loop conformations using continuum dielectric calculations. Using multiple conformations, we showed that the protonation states of titratable groups in the flexible loops can depend on the loop conformation. This, in turn, will affect ligand binding and calculations such as the multiple copy simultaneous search (MCSS) method for small functional group binding. This illustrates the importance of accurately determining the protonation state of the protein prior to the calculation