26 results on '"Poepsel S"'
Search Results
2. H3K36 tri-methylated nucleosome LEDGF PWWP domain complex
- Author
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Koutna, E., primary, Lux, V., additional, Novacek, J., additional, Srb, P., additional, Hexnerova, R., additional, Skerlova, J., additional, Poepsel, S., additional, and Veverka, V., additional
- Published
- 2023
- Full Text
- View/download PDF
3. H3K36 di-methylated nucleosome LEDGF PWWP domain complex
- Author
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Koutna, E., primary, Lux, V., additional, Novacek, J., additional, Srb, P., additional, Hexnerova, R., additional, Skerlova, J., additional, Poepsel, S., additional, and Veverka, V., additional
- Published
- 2023
- Full Text
- View/download PDF
4. Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition
- Author
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Winkler, R., Mägdefrau, A.S., Piskor, E.M., Kleemann, M., Beyer, M., Linke, K., Hansen, L., Schaffer, A.M., Hoffmann, M.E., Poepsel, S., Heyd, F., Beli, P., Möröy, T., Mahboobi, S., Krämer, O.H., Kosan, C., and Universitat Autònoma de Barcelona
- Subjects
Cancer Research ,Lymphoma, B-Cell ,MYC interaction network ,Histone Deacetylase 6 ,Histone Deacetylases ,Mice ,Tubulin ,Genetics ,medicine ,Animals ,Humans ,B-cell lymphoma ,Molecular Biology ,Heat-Shock Proteins ,Chemistry ,Cancer ,Acetylation ,Oncogenes ,500 Naturwissenschaften und Mathematik::570 Biowissenschaften ,Biologie::570 Biowissenschaften ,Biologie ,HDAC6 ,HSP40 Heat-Shock Proteins ,medicine.disease ,Lymphoma ,Histone Deacetylase Inhibitors ,Apoptosis ,Cancer cell ,Cancer research ,DNAJA3 ,Transcription Factors - Abstract
RW was supported by a scholarship from the Carl Zeiss Foundation. CK received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), GRK 1715. E-MP was supported by a Landesgraduiertenstipendium (Friedrich Schiller University Jena). Work done in the group of OHK was done by MB and is funded by DFG, Project-ID 393547839-SFB 1361 and DFG, GRK 2291/9-1, project number 427404172. Open Access funding enabled and organized by Projekt DEAL. Overexpression of MYC is a genuine cancer driver in lymphomas and related to poor prognosis. However, therapeutic targeting of the transcription factor MYC remains challenging. Here, we show that inhibition of the histone deacetylase 6 (HDAC6) using the HDAC6 inhibitor Marbostat-100 (M-100) reduces oncogenic MYC levels and prevents lymphomagenesis in a mouse model of MYC-induced aggressive B-cell lymphoma. M-100 specifically alters protein-protein interactions by switching the acetylation state of HDAC6 substrates, such as tubulin. Tubulin facilitates nuclear import of MYC, and MYC-dependent B-cell lymphoma cells rely on continuous import of MYC due to its high turn-over. Acetylation of tubulin impairs this mechanism and enables proteasomal degradation of MYC. M-100 targets almost exclusively B-cell lymphoma cells with high levels of MYC whereas non-tumor cells are not affected. M-100 induces massive apoptosis in human and murine MYC-overexpressing B-cell lymphoma cells. We identified the heat-shock protein DNAJA3 as an interactor of tubulin in an acetylation-dependent manner and overexpression of DNAJA3 resulted in a pronounced degradation of MYC. We propose a mechanism by which DNAJA3 associates with hyperacetylated tubulin in the cytoplasm to control MYC turnover. Taken together, our data demonstrate a beneficial role of HDAC6 inhibition in MYC-dependent B-cell lymphoma.
- Published
- 2022
5. PRC2-AEBP2-JARID2 bound to H2AK119ub1 nucleosome
- Author
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Kasinath, V., primary, Nogales, E., additional, Beck, C., additional, Sauer, P., additional, Poepsel, S., additional, Kosmatka, J., additional, Faini, M., additional, Toso, D., additional, and Aebersold, R., additional
- Published
- 2021
- Full Text
- View/download PDF
6. Histone H3 recognition by nucleosome-bound PRC2 subunit EZH2.
- Author
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Finogenova, K., primary, Benda, C., additional, Schaefer, I.B., additional, Poepsel, S., additional, Strauss, M., additional, and Mueller, J., additional
- Published
- 2020
- Full Text
- View/download PDF
7. Cryo-EM structure of PRC2 bound to cofactors AEBP2 and JARID2 in the Extended Active State
- Author
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Kasinath, V., primary, Faini, M., additional, Poepsel, S., additional, Reif, D., additional, Feng, A., additional, Stjepanovic, G., additional, Aebersold, R., additional, and Nogales, E., additional
- Published
- 2018
- Full Text
- View/download PDF
8. Cryo-EM structure of PRC2 bound to cofactors AEBP2 and JARID2 in the Compact Active State
- Author
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Kasinath, V., primary, Faini, M., additional, Poepsel, S., additional, Reif, D., additional, Feng, A., additional, Stjepanovic, G., additional, Aebersold, R., additional, and Nogales, E., additional
- Published
- 2018
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9. Human high temperature requirement serine protease A1 (HTRA1) degrades tau protein aggregates
- Author
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Michael Ehrmann, Tim Clausen, Patrick Hauske, Nina Schmidt, Rupert Egensperger, Robert Huber, Leif Dehmelt, Simon Pöpsel, Alfonso Baldi, Annette Tennstaedt, Linda Truebestein, Hanna Ksiezak-Reding, Roland Brandt, Anca Tirniceriu, Markus Kaiser, Anke Brockmann, Barbara Saccà, Inga Irle, Christof M. Niemeyer, Tennstaedt, A, Poepsel, S, Truebestein, L, Hauske, P, Brockmann, A, Schmidt, N, Irle, I, Sacca, B, Niemeyer, Cm, Brandt, R, Ksiezak Reding, H, Tirniceriu, Al, Egensperger, R, Baldi, Alfonso, Dehmelt, L, Kaiser, M, Huber, R, Clausen, T, and Ehrmann, M.
- Subjects
Protein Folding ,Proteases ,medicine.medical_treatment ,Proteolysis ,Tau protein ,Nerve Tissue Proteins ,tau Proteins ,Protein aggregation ,Protein degradation ,Biochemistry ,Gene Expression Regulation, Enzymologic ,Neurites ,medicine ,Humans ,Molecular Biology ,Serine protease ,Protease ,biology ,medicine.diagnostic_test ,Serine Endopeptidases ,Brain ,High-Temperature Requirement A Serine Peptidase 1 ,Cell Biology ,eye diseases ,Cell biology ,Tauopathies ,Protein Synthesis and Degradation ,biology.protein ,Protein folding ,Biologie - Abstract
Protective proteases are key elements of protein quality control pathways that are up-regulated, for example, under various protein folding stresses. These proteases are employed to prevent the accumulation and aggregation of misfolded proteins that can impose severe damage to cells. The high temperature requirement A (HtrA) family of serine proteases has evolved to perform important aspects of ATP-independent protein quality control. So far, however, no HtrA protease is known that degrades protein aggregates. We show here that human HTRA1 degrades aggregated and fibrillar tau, a protein that is critically involved in various neurological disorders. Neuronal cells and patient brains accumulate less tau, neurofibrillary tangles, and neuritic plaques, respectively, when HTRA1 is expressed at elevated levels. Furthermore, HTRA1 mRNA and HTRA1 activity are up-regulated in response to elevated tau concentrations. These data suggest that HTRA1 is performing regulated proteolysis during protein quality control, the implications of which are discussed. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
- Published
- 2012
10. Activation of automethylated PRC2 by dimerization on chromatin.
- Author
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Sauer PV, Pavlenko E, Cookis T, Zirden LC, Renn J, Singhal A, Hunold P, Hoehne-Wiechmann MN, van Ray O, Kaschani F, Kaiser M, Hänsel-Hertsch R, Sanbonmatsu KY, Nogales E, and Poepsel S
- Abstract
Polycomb repressive complex 2 (PRC2) is an epigenetic regulator that trimethylates lysine 27 of histone 3 (H3K27me3) and is essential for embryonic development and cellular differentiation. H3K27me3 is associated with transcriptionally repressed chromatin and is established when PRC2 is allosterically activated upon methyl-lysine binding by the regulatory subunit EED. Automethylation of the catalytic subunit enhancer of zeste homolog 2 (EZH2) stimulates its activity by an unknown mechanism. Here, we show that human PRC2 forms a dimer on chromatin in which an inactive, automethylated PRC2 protomer is the allosteric activator of a second PRC2 that is poised to methylate H3 of a substrate nucleosome. Functional assays support our model of allosteric trans-autoactivation via EED, suggesting a previously unknown mechanism mediating context-dependent activation of PRC2. Our work showcases the molecular mechanism of auto-modification-coupled dimerization in the regulation of chromatin-modifying complexes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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11. Remodeling of the endothelial cell transcriptional program via paracrine and DNA-binding activities of MPO.
- Author
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Zheng R, Moynahan K, Georgomanolis T, Pavlenko E, Geissen S, Mizi A, Grimm S, Nemade H, Rehimi R, Bastigkeit J, Lackmann JW, Adam M, Rada-Iglesias A, Nuernberg P, Klinke A, Poepsel S, Baldus S, Papantonis A, and Kargapolova Y
- Abstract
Myeloperoxidase (MPO) is an enzyme that functions in host defense. MPO is released into the vascular lumen by neutrophils during inflammation and may adhere and subsequently penetrate endothelial cells (ECs) coating vascular walls. We show that MPO enters the nucleus of ECs and binds chromatin independently of its enzymatic activity. MPO drives chromatin decondensation at its binding sites and enhances condensation at neighboring regions. It binds loci relevant for endothelial-to-mesenchymal transition (EndMT) and affects the migratory potential of ECs. Finally, MPO interacts with the RNA-binding factor ILF3 thereby affecting its relative abundance between cytoplasm and nucleus. This interaction leads to change in stability of ILF3-bound transcripts. MPO-knockout mice exhibit reduced number of ECs at scar sites following myocardial infarction, indicating reduced neovascularization. In summary, we describe a non-enzymatic role for MPO in coordinating EndMT and controlling the fate of endothelial cells through direct chromatin binding and association with co-factors., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
12. Streptavidin-Affinity Grid Fabrication for Cryo-Electron Microscopy Sample Preparation.
- Author
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Cookis T, Sauer P, Poepsel S, Han BG, Herbst DA, Glaeser R, and Nogales E
- Subjects
- Cryoelectron Microscopy methods, Streptavidin chemistry, Water, Carbon chemistry, Biotin
- Abstract
Streptavidin affinity grids provide strategies to overcome many commonly encountered cryo-electron microscopy (cryo-EM) sample preparation challenges, including sample denaturation and preferential orientations that can occur due to the air-water interface. Streptavidin affinity grids, however, are currently utilized by few cryo-EM labs because they are not commercially available and require a careful fabrication process. Two-dimensional streptavidin crystals are grown onto a biotinylated lipid monolayer that is applied directly to standard holey-carbon cryo-EM grids. The high-affinity interaction between streptavidin and biotin allows for the subsequent binding of biotinylated samples that are protected from the air-water interface during cryo-EM sample preparation. Additionally, these grids provide a strategy for concentrating samples available in limited quantities and purifying protein complexes of interest directly on the grids. Here, a step-by-step, optimized protocol is provided for the robust fabrication of streptavidin affinity grids for use in cryo-EM and negative-stain experiments. Additionally, a trouble-shooting guide is included for commonly experienced challenges to make the use of streptavidin affinity grids more accessible to the larger cryo-EM community.
- Published
- 2023
- Full Text
- View/download PDF
13. Multivalency of nucleosome recognition by LEDGF.
- Author
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Koutná E, Lux V, Kouba T, Škerlová J, Nováček J, Srb P, Hexnerová R, Šváchová H, Kukačka Z, Novák P, Fábry M, Poepsel S, and Veverka V
- Abstract
Eukaryotic transcription is dependent on specific histone modifications. Their recognition by chromatin readers triggers complex processes relying on the coordinated association of transcription regulatory factors. Although various modification states of a particular histone residue often lead to differential outcomes, it is not entirely clear how they are discriminated. Moreover, the contribution of intrinsically disordered regions outside of the specialized reader domains to nucleosome binding remains unexplored. Here, we report the structures of a PWWP domain from transcriptional coactivator LEDGF in complex with the H3K36 di- and trimethylated nucleosome, indicating that both methylation marks are recognized by PWWP in a highly conserved manner. We identify a unique secondary interaction site for the PWWP domain at the interface between the acidic patch and nucleosomal DNA that might contribute to an H3K36-methylation independent role of LEDGF. We reveal DNA interacting motifs in the intrinsically disordered region of LEDGF that discriminate between the intra- or extranucleosomal DNA but remain dynamic in the context of dinucleosomes. The interplay between the LEDGF H3K36-methylation reader and protein binding module mediated by multivalent interactions of the intrinsically disordered linker with chromatin might help direct the elongation machinery to the vicinity of RNA polymerase II, thereby facilitating productive elongation., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2023
- Full Text
- View/download PDF
14. Activation of automethylated PRC2 by dimerization on chromatin.
- Author
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Sauer PV, Pavlenko E, Cookis T, Zirden LC, Renn J, Singhal A, Hunold P, Hoehne MN, van Ray O, Hänsel-Hertsch R, Sanbonmatsu KY, Nogales E, and Poepsel S
- Abstract
Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator that trimethylates lysine 27 of histone 3 (H3K27me3) and is essential for embryonic development and cellular differentiation. H3K27me3 is associated with transcriptionally repressed chromatin and is established when PRC2 is allosterically activated upon methyl-lysine binding by the regulatory subunit EED. Automethylation of the catalytic subunit EZH2 stimulates its activity by an unknown mechanism. Here, we show that PRC2 forms a dimer on chromatin in which an inactive, automethylated PRC2 protomer is the allosteric activator of a second PRC2 that is poised to methylate H3 of a substrate nucleosome. Functional assays support our model of allosteric trans -autoactivation via EED, suggesting a novel mechanism mediating context-dependent activation of PRC2. Our work showcases the molecular mechanism of auto-modification coupled dimerization in the regulation of chromatin modifying complexes., Competing Interests: Competing interests The authors declare no competing interests.
- Published
- 2023
- Full Text
- View/download PDF
15. Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition.
- Author
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Winkler R, Mägdefrau AS, Piskor EM, Kleemann M, Beyer M, Linke K, Hansen L, Schaffer AM, Hoffmann ME, Poepsel S, Heyd F, Beli P, Möröy T, Mahboobi S, Krämer OH, and Kosan C
- Subjects
- Acetylation, Animals, HSP40 Heat-Shock Proteins metabolism, Heat-Shock Proteins metabolism, Histone Deacetylase 6 metabolism, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases genetics, Histone Deacetylases metabolism, Humans, Mice, Transcription Factors metabolism, Lymphoma, B-Cell drug therapy, Lymphoma, B-Cell genetics, Tubulin metabolism
- Abstract
Overexpression of MYC is a genuine cancer driver in lymphomas and related to poor prognosis. However, therapeutic targeting of the transcription factor MYC remains challenging. Here, we show that inhibition of the histone deacetylase 6 (HDAC6) using the HDAC6 inhibitor Marbostat-100 (M-100) reduces oncogenic MYC levels and prevents lymphomagenesis in a mouse model of MYC-induced aggressive B-cell lymphoma. M-100 specifically alters protein-protein interactions by switching the acetylation state of HDAC6 substrates, such as tubulin. Tubulin facilitates nuclear import of MYC, and MYC-dependent B-cell lymphoma cells rely on continuous import of MYC due to its high turn-over. Acetylation of tubulin impairs this mechanism and enables proteasomal degradation of MYC. M-100 targets almost exclusively B-cell lymphoma cells with high levels of MYC whereas non-tumor cells are not affected. M-100 induces massive apoptosis in human and murine MYC-overexpressing B-cell lymphoma cells. We identified the heat-shock protein DNAJA3 as an interactor of tubulin in an acetylation-dependent manner and overexpression of DNAJA3 resulted in a pronounced degradation of MYC. We propose a mechanism by which DNAJA3 associates with hyperacetylated tubulin in the cytoplasm to control MYC turnover. Taken together, our data demonstrate a beneficial role of HDAC6 inhibition in MYC-dependent B-cell lymphoma., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
16. Functions and Interactions of Mammalian KDM5 Demethylases.
- Author
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Pavlenko E, Ruengeler T, Engel P, and Poepsel S
- Abstract
Mammalian histone demethylases of the KDM5 family are mediators of gene expression dynamics during developmental, cellular differentiation, and other nuclear processes. They belong to the large group of JmjC domain containing, 2-oxoglutarate (2-OG) dependent oxygenases and target methylated lysine 4 of histone H3 (H3K4me1/2/3), an epigenetic mark associated with active transcription. In recent years, KDM5 demethylases have gained increasing attention due to their misregulation in many cancer entities and are intensively explored as therapeutic targets. Despite these implications, the molecular basis of KDM5 function has so far remained only poorly understood. Little is known about mechanisms of nucleosome recognition, the recruitment to genomic targets, as well as the local regulation of demethylase activity. Experimental evidence suggests close physical and functional interactions with epigenetic regulators such as histone deacetylase (HDAC) containing complexes, as well as the retinoblastoma protein (RB). To understand the regulation of KDM5 proteins in the context of chromatin, these interactions have to be taken into account. Here, we review the current state of knowledge on KDM5 function, with a particular emphasis on molecular interactions and their potential implications. We will discuss and outline open questions that need to be addressed to better understand histone demethylation and potential demethylation-independent functions of KDM5s. Addressing these questions will increase our understanding of histone demethylation and allow us to develop strategies to target individual KDM5 enzymes in specific biological and disease contexts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pavlenko, Ruengeler, Engel and Poepsel.)
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- 2022
- Full Text
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17. JARID2 and AEBP2 regulate PRC2 in the presence of H2AK119ub1 and other histone modifications.
- Author
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Kasinath V, Beck C, Sauer P, Poepsel S, Kosmatka J, Faini M, Toso D, Aebersold R, and Nogales E
- Subjects
- Animals, Cryoelectron Microscopy, Gene Expression Regulation, Histones metabolism, Humans, Nucleosomes metabolism, PR-SET Domains, Polycomb Repressive Complex 2 chemistry, Ubiquitin metabolism, Xenopus, Histone Code, Polycomb Repressive Complex 2 metabolism, Repressor Proteins metabolism
- Abstract
Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) cooperate to determine cell identity by epigenetic gene expression regulation. However, the mechanism of PRC2 recruitment by means of recognition of PRC1-mediated H2AK119ub1 remains poorly understood. Our PRC2 cryo-electron microscopy structure with cofactors JARID2 and AEBP2 bound to a H2AK119ub1-containing nucleosome reveals a bridge helix in EZH2 that connects the SET domain, H3 tail, and nucleosomal DNA. JARID2 and AEBP2 each interact with one ubiquitin and the H2A-H2B surface. JARID2 stimulates PRC2 through interactions with both the polycomb protein EED and the H2AK119-ubiquitin, whereas AEBP2 has an additional scaffolding role. The presence of these cofactors partially overcomes the inhibitory effect that H3K4me3 and H3K36me3 exert on core PRC2 (in the absence of cofactors). Our results support a key role for JARID2 and AEBP2 in the cross-talk between histone modifications and PRC2 activity., (Copyright © 2021, American Association for the Advancement of Science.)
- Published
- 2021
- Full Text
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18. Structural basis for PRC2 decoding of active histone methylation marks H3K36me2/3.
- Author
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Finogenova K, Bonnet J, Poepsel S, Schäfer IB, Finkl K, Schmid K, Litz C, Strauss M, Benda C, and Müller J
- Subjects
- Animals, Baculoviridae, Catalytic Domain, Cell Line, Cryoelectron Microscopy, Drosophila Proteins genetics, Drosophila melanogaster, Gene Expression Regulation, Histone-Lysine N-Methyltransferase genetics, Humans, Methylation, Models, Molecular, Mutation, Protein Conformation, Protein Processing, Post-Translational, Xenopus, Drosophila Proteins metabolism, Histone-Lysine N-Methyltransferase metabolism, Histones metabolism
- Abstract
Repression of genes by Polycomb requires that PRC2 modifies their chromatin by trimethylating lysine 27 on histone H3 (H3K27me3). At transcriptionally active genes, di- and tri-methylated H3K36 inhibit PRC2. Here, the cryo-EM structure of PRC2 on dinucleosomes reveals how binding of its catalytic subunit EZH2 to nucleosomal DNA orients the H3 N-terminus via an extended network of interactions to place H3K27 into the active site. Unmodified H3K36 occupies a critical position in the EZH2-DNA interface. Mutation of H3K36 to arginine or alanine inhibits H3K27 methylation by PRC2 on nucleosomes in vitro . Accordingly, Drosophila H3K36A and H3K36R mutants show reduced levels of H3K27me3 and defective Polycomb repression of HOX genes. The relay of interactions between EZH2, the nucleosomal DNA and the H3 N-terminus therefore creates the geometry that permits allosteric inhibition of PRC2 by methylated H3K36 in transcriptionally active chromatin., Competing Interests: KF, JB, SP, IS, KF, KS, CL, MS, CB, JM No competing interests declared, (© 2020, Finogenova et al.)
- Published
- 2020
- Full Text
- View/download PDF
19. Anesthetic Management of a Laboring Patient With a Closed-Loop Stimulation Pacemaker: A Case Report.
- Author
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Ray SB and Poepsel S
- Subjects
- Adult, Female, Humans, Pregnancy, Anesthetics standards, Arrhythmias, Cardiac therapy, Labor Pain drug therapy, Pacemaker, Artificial adverse effects, Pain Management standards, Practice Guidelines as Topic, Pregnant Women
- Abstract
A new generation of cardiac implantable devices, known as Closed Loop Stimulation pacemakers, are now utilized to reduce episodes of bradycardia, syncope, and tachycardia in pregnant women. The device functions differently than conventional pacemakers by responding to changes in the patient`s cardiac output and heart rate based on physiologic demands and acute mental stress. Increased metabolic demands, including physiologic stress often accompany pregnancy, labor, and delivery. The Certified Registered Nurse Anesthetist providing analgesia and anesthesia for the laboring patient with CLS pacemaker may encounter rapid changes in heart rates, initiation of pacing modes, and hypotension resulting from reduced cardiac outputs. The ability to differentiate and diagnose the causes of hemodynamic changes and provide appropriate interventions is essential to optimize maternal and fetal outcomes. This case report details the anesthetic management of a laboring twenty-five-year-old primigravida with an implantable CLS pacemaker secondary to a history of third degree heart block, cardiac ablation after supraventricular tachycardia, and seizures. The parturient experienced intermittent pacing after neuraxial analgesia. Anticipation of the CLS pacemaker's response to the parturient's physiological and emotional response during the labor process will be discussed including recommendations to optimize maternal and fetal outcomes., Competing Interests: The authors have declared no financial relationships with any commercial entity related to the content of this article. The authors did not discuss off-label use within the article. Disclosure statements are available for viewing upon request., (Copyright© by the American Association of Nurse Anesthetists.)
- Published
- 2019
20. Recent Structural Insights into Polycomb Repressive Complex 2 Regulation and Substrate Binding.
- Author
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Kasinath V, Poepsel S, and Nogales E
- Subjects
- Humans, Methylation, Models, Molecular, Protein Conformation, Substrate Specificity, Gene Expression Regulation, Histones metabolism, Methyltransferases metabolism, Polycomb Repressive Complex 2 chemistry, Polycomb Repressive Complex 2 metabolism, Repressor Proteins metabolism
- Abstract
Polycomb group proteins are transcriptional repressors controlling gene expression patterns and maintaining cell type identity. The chemical modifications of histones and DNA caused by the regulated activity of chromatin-modifying enzymes such as Polycomb help establish and maintain such expression patterns. Polycomb repressive complex 2 (PRC2) is the only known methyltransferase specific for histone H3 lysine 27 (H3K27) and catalyzes its trimethylation leading to the repressive H3K27me3 mark. Structural biology has made important contributions to our understanding of the molecular mechanisms that ensure the spatiotemporal regulation of PRC2 activity and the establishment of inactive chromatin domains marked by H3K27me3. In this review, we discuss the recent structural studies that have advanced our understanding of PRC2 function, in particular the roles of intersubunit interactions in complex assembly and the regulation of methyltransferase activity, as well as the mechanism of local H3K27me3 spreading leading to repressive domains.
- Published
- 2019
- Full Text
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21. Near-atomic model of microtubule-tau interactions.
- Author
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Kellogg EH, Hejab NMA, Poepsel S, Downing KH, DiMaio F, and Nogales E
- Subjects
- Conserved Sequence, Cryoelectron Microscopy, Humans, Phosphorylation, Phylogeny, Polymerization, Tandem Repeat Sequences, tau Proteins classification, Microtubules chemistry, Models, Chemical, tau Proteins chemistry
- Abstract
Tau is a developmentally regulated axonal protein that stabilizes and bundles microtubules (MTs). Its hyperphosphorylation is thought to cause detachment from MTs and subsequent aggregation into fibrils implicated in Alzheimer's disease. It is unclear which tau residues are crucial for tau-MT interactions, where tau binds on MTs, and how it stabilizes them. We used cryo-electron microscopy to visualize different tau constructs on MTs and computational approaches to generate atomic models of tau-tubulin interactions. The conserved tubulin-binding repeats within tau adopt similar extended structures along the crest of the protofilament, stabilizing the interface between tubulin dimers. Our structures explain the effect of phosphorylation on MT affinity and lead to a model of tau repeats binding in tandem along protofilaments, tethering together tubulin dimers and stabilizing polymerization interfaces., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
- Full Text
- View/download PDF
22. Structures of human PRC2 with its cofactors AEBP2 and JARID2.
- Author
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Kasinath V, Faini M, Poepsel S, Reif D, Feng XA, Stjepanovic G, Aebersold R, and Nogales E
- Subjects
- Cryoelectron Microscopy, Histones chemistry, Humans, Methylation, Polycomb Repressive Complex 2 ultrastructure, Protein Binding, Protein Conformation, Repressor Proteins ultrastructure, Polycomb Repressive Complex 2 chemistry, Repressor Proteins chemistry
- Abstract
Transcriptionally repressive histone H3 lysine 27 methylation by Polycomb repressive complex 2 (PRC2) is essential for cellular differentiation and development. Here we report cryo-electron microscopy structures of human PRC2 in a basal state and two distinct active states while in complex with its cofactors JARID2 and AEBP2. Both cofactors mimic the binding of histone H3 tails. JARID2, methylated by PRC2, mimics a methylated H3 tail to stimulate PRC2 activity, whereas AEBP2 interacts with the RBAP48 subunit, mimicking an unmodified H3 tail. SUZ12 interacts with all other subunits within the assembly and thus contributes to the stability of the complex. Our analysis defines the complete architecture of a functionally relevant PRC2 and provides a structural framework to understand its regulation by cofactors, histone tails, and RNA., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
- Full Text
- View/download PDF
23. Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes.
- Author
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Poepsel S, Kasinath V, and Nogales E
- Subjects
- Chromatin chemistry, Cross-Linking Reagents chemistry, Crystallography, X-Ray, DNA chemistry, Enhancer of Zeste Homolog 2 Protein chemistry, Epigenesis, Genetic, Gene Silencing, Histones chemistry, Humans, Lysine chemistry, Models, Molecular, Neoplasm Proteins, Protein Binding, Protein Domains, Recombinant Proteins chemistry, Repressor Proteins chemistry, Retinoblastoma-Binding Protein 4 chemistry, Transcription Factors, Cryoelectron Microscopy, Nucleosomes chemistry, Polycomb Repressive Complex 2 chemistry
- Abstract
Epigenetic regulation is mediated by protein complexes that couple recognition of chromatin marks to activity or recruitment of chromatin-modifying enzymes. Polycomb repressive complex 2 (PRC2), a gene silencer that methylates lysine 27 of histone H3, is stimulated upon recognition of its own catalytic product and has been shown to be more active on dinucleosomes than H3 tails or single nucleosomes. These properties probably facilitate local H3K27me2/3 spreading, causing heterochromatin formation and gene repression. Here, cryo-EM reconstructions of human PRC2 bound to bifunctional dinucleosomes show how a single PRC2, via interactions with nucleosomal DNA, positions the H3 tails of the activating and substrate nucleosome to interact with the EED subunit and the SET domain of EZH2, respectively. We show how the geometry of the PRC2-DNA interactions allows PRC2 to accommodate varying lengths of the linker DNA between nucleosomes. Our structures illustrate how an epigenetic regulator engages with a complex chromatin substrate.
- Published
- 2018
- Full Text
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24. Determinants of amyloid fibril degradation by the PDZ protease HTRA1.
- Author
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Poepsel S, Sprengel A, Sacca B, Kaschani F, Kaiser M, Gatsogiannis C, Raunser S, Clausen T, and Ehrmann M
- Subjects
- Amyloid genetics, Amyloid beta-Peptides genetics, Biological Transport, Gene Expression, HEK293 Cells, High-Temperature Requirement A Serine Peptidase 1, Humans, PDZ Domains, Peptide Fragments genetics, Protein Aggregates, Protein Conformation, Proteolysis, Recombinant Fusion Proteins genetics, Serine Endopeptidases genetics, tau Proteins genetics, Amyloid chemistry, Amyloid beta-Peptides chemistry, Peptide Fragments chemistry, Recombinant Fusion Proteins chemistry, Serine Endopeptidases chemistry, tau Proteins chemistry
- Abstract
Excessive aggregation of proteins has a major impact on cell fate and is a hallmark of amyloid diseases in humans. To resolve insoluble deposits and to maintain protein homeostasis, all cells use dedicated protein disaggregation, protein folding and protein degradation factors. Despite intense recent research, the underlying mechanisms controlling this key metabolic event are not well understood. Here, we analyzed how a single factor, the highly conserved serine protease HTRA1, degrades amyloid fibrils in an ATP-independent manner. This PDZ protease solubilizes protein fibrils and disintegrates the fibrillar core structure, allowing productive interaction of aggregated polypeptides with the active site for rapid degradation. The aggregate burden in a cellular model of cytoplasmic tau aggregation is thus reduced. Mechanistic aspects of ATP-independent proteolysis and its implications in amyloid diseases are discussed.
- Published
- 2015
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25. Determinants of structural and functional plasticity of a widely conserved protease chaperone complex.
- Author
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Merdanovic M, Mamant N, Meltzer M, Poepsel S, Auckenthaler A, Melgaard R, Hauske P, Nagel-Steger L, Clarke AR, Kaiser M, Huber R, and Ehrmann M
- Subjects
- Amino Acid Sequence, Bacteria genetics, Bacterial Proteins genetics, Catalytic Domain, Heat-Shock Proteins genetics, Models, Molecular, PDZ Domains, Peptides chemistry, Peptides metabolism, Periplasmic Proteins genetics, Point Mutation, Protein Binding, Protein Folding, Protein Multimerization, Serine Endopeptidases genetics, Bacteria metabolism, Bacterial Proteins chemistry, Bacterial Proteins metabolism, Heat-Shock Proteins chemistry, Heat-Shock Proteins metabolism, Periplasmic Proteins chemistry, Periplasmic Proteins metabolism, Serine Endopeptidases chemistry, Serine Endopeptidases metabolism
- Abstract
Channeling of misfolded proteins into repair, assembly or degradation pathways is often mediated by complex and multifunctional cellular factors. Despite detailed structural information, the underlying regulatory mechanisms governing these factors are not well understood. The extracytoplasmic heat-shock factor DegP (HtrA) is a well-suited model for addressing mechanistic issues, as it is regulated by the common mechanisms of allostery and activation by oligomerization. Site-directed mutagenesis combined with refolding and oligomerization studies of chemically denatured DegP revealed how substrates trigger the conversion of the resting conformation into the active conformation. Binding of specific peptides to PDZ domain-1 causes a local rearrangement that is allosterically transmitted to the substrate-binding pocket of the protease domain. This activated state readily assembles into larger oligomeric particles, thus stabilizing the catalytically active form and providing a degradation cavity for protein substrates. The implications of these data for the mechanism of protein quality control are discussed.
- Published
- 2010
- Full Text
- View/download PDF
26. Structure, function and regulation of the conserved serine proteases DegP and DegS of Escherichia coli.
- Author
-
Meltzer M, Hasenbein S, Mamant N, Merdanovic M, Poepsel S, Hauske P, Kaiser M, Huber R, Krojer T, Clausen T, and Ehrmann M
- Subjects
- Escherichia coli genetics, Gene Expression Regulation, Bacterial, Escherichia coli enzymology, Escherichia coli Proteins chemistry, Escherichia coli Proteins metabolism, Heat-Shock Proteins chemistry, Heat-Shock Proteins metabolism, Periplasmic Proteins chemistry, Periplasmic Proteins metabolism, Serine Endopeptidases chemistry, Serine Endopeptidases metabolism
- Abstract
Two members of the widely conserved HtrA family of serine proteases, DegP and DegS, are key players in extracytoplasmic protein quality control. The underlying mechanisms of their main functions in stress sensing, regulation and protection during the unfolded protein response are discussed.
- Published
- 2009
- Full Text
- View/download PDF
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