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FEBS Journal

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https://www.readbyqxmd.com/read/28231404/express-or-repress-the-transcriptional-dilemma-of-damaged-chromatin
#1
Ilaria Capozzo, Fabio Iannelli, Sofia Francia, Fabrizio d'Adda di Fagagna
The fine modulation of transcriptional activity around DNA lesions is essential to carefully regulate the crosstalk between transcription, the DNA damage response, and DNA repair, particularly when the lesion occurs next to, or within, actively transcribed genes. Recently, several studies have been carried out to investigate how DNA lesions have an impact on local transcription, but the emerging model remains incomplete. Transcription of genes around damaged DNA is actively down-regulated by the DNA damage response through different mechanisms, which appear specific to the chromatin context, the type of DNA damage or its complexity...
February 23, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28222489/characterization-of-a-novel-signal-transducer-element-intrinsic-to-class-iiia-b-adenylate-cyclases-and-guanylate-cyclases
#2
Miriam Ziegler, Jens Bassler, Stephanie Beltz, Anita Schultz, Andrei N Lupas, Joachim E Schultz
Adenylate cyclases (ACs) are signalling proteins that produce the second messenger cAMP. Class III ACs comprises four groups (class IIIa-d); of these, class IIIa and IIIb ACs have been identified in bacteria and eukaryotes. Many class IIIa ACs are anchored to membranes via hexahelical domains. In eukaryotic ACs, membrane anchors are well conserved, suggesting that this region possesses important functional characteristics that are as yet unknown. To address this question, we replaced the hexahelical membrane anchor of the mycobacterial AC Rv1625c by the hexahelical quorum-sensing receptor from Legionella, LqsS...
February 21, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28222482/functional-reconstitution-of-the-mycobacterium-tuberculosis-long-chain-acyl-coa-carboxylase-from-multiple-acyl-coa-subunits
#3
Bernardo Bazet Lyonnet, Lautaro Diacovich, Gabriela Gago, Lucie Spina, Fabienne Bardou, Anne Lemassu, Annaïk Quémard, Hugo Gramajo
Mycobacterium tuberculosis produces a large number of structurally diverse lipids that have been implicated in the pathogenicity, persistence and antibiotic resistance of this organism. Most building blocks involved in the biosynthesis of all these lipids are generated by acyl-CoA carboxylases (ACCase) whose subunit composition and physiological roles have not yet been clearly established. A rather controversial data in the literature refers to the exact protein composition and substrate specificity of the enzyme complex that produces the long-chain α-carboxy-acyl-CoAs; one of the substrates involved in the last step of condensation mediated by the polyketide synthase Pks13 to synthesize mature mycolic acids...
February 21, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28207202/the-polar-warhead-of-a-trim24-bromodomain-inhibitor-rearranges-a-water-mediated-interaction-network
#4
Jiuyang Liu, Fudong Li, Hongyu Bao, Yiyang Jiang, Shuya Zhang, Rongsheng Ma, Jia Gao, Jihui Wu, Ke Ruan
Tripartite motif-containing protein 24 (TRIM24) is closely correlated with multiple cancers, and a recent study demonstrated that the bromodomain of TRIM24 is essential for the proliferation of lethal castration-resistant prostate cancer. Here, we identify three new inhibitors of the TRIM24 bromodomain using NMR fragment-based screening. The crystal structures of two new inhibitors in complex with the TRIM24 bromodomain reveal that the water-bridged interaction network is conserved in the same fashion as those for known benzoimidazolone inhibitors...
February 16, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28207191/cysteine-proteases-in-atherosclerosis
#5
REVIEW
Tommy Weiss Sadan, Israel Gotsman, Galia Blum
Atherosclerosis predisposes patients to cardiovascular diseases, such as myocardial infarction and stroke. Instigation of vascular injury is triggered by retention of lipids and inflammatory cells in the vascular endothelium. Whereas these vascular lesions develop in young adults and are mostly considered harmless, over time persistent inflammatory and remodeling processes will ultimately damage the arterial wall and cause a thrombotic event due to exposure of tissue factors into the lumen. Evidence from human tissues and pre-clinical animal models have clearly established the role of cathepsin cysteine proteases in the development and progression of vascular lesions...
February 16, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28207183/combining-the-auxin-inducible-degradation-system-with-crispr-cas9-based-genome-editing-for-the-conditional-depletion-of-endogenous-drosophila-melanogaster-proteins
#6
Melinda Bence, Ferenc Jankovics, Tamás Lukácsovich, Miklós Erdélyi
Inducible protein degradation techniques have considerable advantages over classical genetic approaches, which generate loss-of-function phenotypes at the gene or mRNA level. The plant-derived auxin-inducible degradation system (AID) is a promising technique which enables the degradation of target proteins tagged with the AID motif in non-plant cells. Here, we present a detailed characterization of this method employed during the adult oogenesis of Drosophila. Furthermore, with the help of CRISPR/Cas9-based genome editing, we improve the utility of the AID system in the conditional elimination of endogenously expressed proteins...
February 16, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28196299/activity-based-probes-for-the-ubiquitin-conjugation-deconjugation-machinery-new-chemistries-new-tools-and-new-insights
#7
REVIEW
David S Hewings, John A Flygare, Matthew Bogyo, Ingrid E Wertz
The reversible post-translational modification of proteins by ubiquitin and ubiquitin-like proteins regulates almost all cellular processes, by affecting protein degradation, localization, and complex formation. Deubiquitinases (DUBs) are proteases that remove ubiquitin modifications or cleave ubiquitin chains. Most DUBs are cysteine proteases, which makes them well suited for study by activity-based probes. These DUB probes report on deubiquitinase activity by reacting covalently with the active site in an enzyme-catalyzed manner...
February 14, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28196297/targeting-invasive-properties-of-melanoma-cells
#8
REVIEW
Imanol Arozarena, Claudia Wellbrock
Melanoma is a skin cancer notorious for its metastatic potential. As an initial step of the metastatic cascade melanoma cells part from the primary tumour and invade the surrounding tissue, which is crucial for their dissemination and the formation of distant secondary tumours. Over the last two decades our understanding of both, general and melanoma specific mechanisms of invasion has significantly improved, but to date no efficient therapeutic strategy tackling the invasive properties of melanoma cells has reached the clinic...
February 14, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28194887/atgl-deficiency-induces-podocyte-apoptosis-and-leads-to-glomerular-filtration-barrier-damage
#9
Wen Chen, Youzhao Jiang, Jian Han, Jiongyu Hu, Ting He, Tiantian Yan, Huang Na, Qiong Zhang, Hao Mei, Yong Liao, Yuesheng Huang, Bing Chen
Abnormal lipid metabolism, renal lipid accumulation and lipotoxicity are associated with the pathological features of glomerulopathy. However, the mechanisms by which lipid accumulation leads to the development or progression of this disease have not been fully elucidated. In this work, we have identified a role for the rate-limiting enzyme in lipolysis, adipose triglyceride lipase (ATGL; also called patatin-like phospholipase domain-containing protein 2(PNPLP2), in renal lipid metabolism and kidney disease...
February 14, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28186693/science-narcissism-and-the-quest-for-visibility
#10
Bruno Lemaitre
Most scientists will admit that there are aspects of science (sometimes called 'politics') that go far beyond scientific rationality but that nevertheless have a tremendous impact on the practice of science. Power struggles and ego battles are, for instance, quite prevalent in the academic world, notably in our so-called elite institutions. At first sight, this might surprise an external observer, because scientists are usually perceived as being modest searchers for the truth and of working collectively for the advancement of science...
February 10, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28165677/structure-of-the-sliding-clamp-from-the-fungal-pathogen-aspergillus-fumigatus-afumpcna-and-interactions-with-human-p21
#11
Andrew C Marshall, Alice J Kroker, Lauren A M Murray, Kahlia Gronthos, Harinda Rajapaksha, Kate L Wegener, John B Bruning
The fungal pathogen Aspergillus fumigatus has been implicated in a drastic increase in life-threatening infections over the past decade. However, compared to other microbial pathogens, little is known about the essential molecular processes of this organism. One such fundamental process is DNA replication. The protein responsible for ensuring processive DNA replication is PCNA (Proliferating Cell Nuclear Antigen, also known as the sliding clamp), which clamps the replicative polymerase to DNA. Here we present the first crystal structure of a sliding clamp from a pathogenic fungus (A...
February 6, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28165668/plant-life-needs-cell-death-but-does-plant-cell-death-need-cys-proteases
#12
REVIEW
Daniela J Sueldo, Renier A L van der Hoorn
Caspases are key regulators of apoptosis in animals. This correlation has driven plant researchers for decades to look for caspases regulating Programmed Cell Death (PCD) in plants. These studies revealed caspase-like activities, caspase-related proteases and cysteine (Cys) proteases regulating PCD in plants, but identified no caspases and no conserved, apoptosis-like death pathway. Here, we critically review the evidence for Cys proteases implicated in PCD in plants. We discuss the role of papain-like Cys proteases, vacuolar processing enzymes and metacaspases in PCD during the development of tracheary elements, seed coat, suspensor and tapetum and during the hypersensitive response...
February 6, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28165666/ultra-high-resolution-structure-and-charge-density-analysis-of-high-potential-iron-sulfur-protein
#13
REVIEW
Kazuki Takeda, Kunio Miki
The high-potential iron-sulfur protein (HiPIP) is a small (~80 residues) soluble metalloprotein functioning as an electron carrier in photosynthetic bacteria. HiPIP has one Fe4 S4 cluster at its molecular center. Its electronic structure is important for understanding electron transport. We recently succeeded in determining an ultra-high-resolution structure and analyzing the charge-density of HiPIP by using X-ray diffraction data at 0.48 Å resolution. The distribution of valence electrons in the iron-sulfur cluster and in the protein environment were clearly visualized, which is the first successful case for metalloproteins...
February 6, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28164464/hydrophobic-domains-of-mouse-polyomavirus-minor-capsid-proteins-promote-membrane-association-and-virus-exit-from-the-er
#14
Sandra Huérfano, Boris Ryabchenko, Hana Spanielová, Jitka Forstová
The minor structural protein VP2 and its shorter variant, VP3, of mouse polyomavirus (MPyV) are essential for virus exit from the ER during viral trafficking to the nucleus. Here, we followed the role of putative hydrophobic domains (HD) of the minor proteins in membrane affinity and viral infectivity. We prepared variants of VP2, each mutated to decrease hydrophobicity of one of three predicted hydrophobic domains: VP2-mHD1, VP2-mHD2 or VP2-mHD3 mutated in HD1 (aa 60-101), HD2 (aa 125-165) or HD3 (aa 287-307), respectively...
February 5, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28132417/noncoding-rnas-and-immune-checkpoints-clinical-implications-as-cancer-therapeutics
#15
REVIEW
Maria A Smolle, Horatiu N Calin, Martin Pichler, George A Calin
A major mechanism of tumor development and progression is silencing of the patient's immune response to cancer-specific antigens. Defects in the so-called cancer immunity cycle may occur at any stage of tumor development. Within the tumor microenvironment, aberrant expression of immune checkpoint molecules with activating or inhibitory effects on T lymphocytes induces immune tolerance and cellular immune escape. Targeting immune checkpoint molecules such as programmed cell death protein 1 (PD-1) and its ligand PD-L1 with specific antibodies has proven to be a major advance in the treatment of several types of cancer...
January 28, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28122162/targeting-proteasomes-in-infectious-organisms-to-combat-disease
#16
REVIEW
Betsaida Bibo-Verdugo, Zhenze Jiang, Conor R Caffrey, Anthony J O'Donoghue
Proteasomes are multisubunit, energy-dependent, proteolytic complexes that play an essential role in intracellular protein turnover. They are present in eukaryotes, archaea, and in some actinobacteria species. Inhibition of proteasome activity has emerged as a powerful strategy for anticancer therapy and three drugs have been approved for treatment of multiple myeloma. These compounds react covalently with a threonine residue located in the active site of a proteasome subunit to block protein degradation. Proteasomes in pathogenic organisms such as Mycobacterium tuberculosis and Plasmodium falciparum also have a nucleophilic threonine residue in the proteasome active site and are therefore sensitive to these anticancer drugs...
January 25, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28118532/regulating-the-balance-between-the-kynurenine-and-serotonin-pathways-of-tryptophan-metabolism
#17
Yang Li, Nan Hu, Dan Yang, Gregory Oxenkrug, Qing Yang
Tryptophan is metabolized along the kynurenine and serotonin pathways, resulting in formation of kynurenine metabolites, neuroactive serotonin and melatonin. Each pathway is critical for maintaining healthy homeostasis. However, the two pathways are extremely unequal in their ability to degrade tryptophan, and little is known about the mechanisms maintaining the balance between them. Here, we demonstrated that in PC12 cells, a change of expression of key genes of one pathway resulted in a change of expression of key genes of the other...
January 24, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28118529/slc25a26-overexpression-impairs-cell-function-via-mtdna-hypermethylation-and-rewiring-of-methyl-metabolism
#18
Alessio Menga, Erika M Palmieri, Antonia Cianciulli, Vittoria Infantino, Massimiliano Mazzone, Antonio Scilimati, Ferdinando Palmieri, Alessandra Castegna, Vito Iacobazzi
Cancer cells down-regulate different genes to take a selective advantage towards invasiveness and/or metastasis formation. The SLC25A26 gene, encoding for the mitochondrial carrier that catalyzes the import of S-adenosylmethionine (SAM) into the mitochondrial matrix required for mitochondrial methylation processes, is down-regulated in cervical cancer cells. In this study we show that SLC25A26 is down-regulated due to gene promoter hypermethylation, as a mechanism to promote cell survival and proliferation...
January 24, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28117557/asp263-missense-variants-perturb-the-active-site-of-human-phosphoglucomutase-1-pgm1
#19
Kyle M Stiers, Abigail C Graham, Bailee N Kain, Lesa J Beamer
The enzyme phosphoglucomutase 1 (PGM1) plays a central role in glucose homeostasis. Clinical studies have identified mutations in human PGM1 as the cause of PGM1 deficiency, an inherited metabolic disease. One residue, Asp263, has two known variants associated with disease: D263G and D263Y. Biochemical studies have shown that these mutants are soluble and well folded, but have significant catalytic impairment. To better understand this catalytic defect, we determined crystal structures of these two missense variants, both of which reveal a similar and indirect structural change due to the loss of a conserved salt bridge between Asp263 and Arg293...
January 24, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28109185/folding-of-intrinsically-disordered-plant-lea-proteins-is-driven-by-glycerol-induced-crowding-and-the-presence-of-membranes
#20
Anne Bremer, Martin Wolff, Anja Thalhammer, Dirk K Hincha
Late embryogenesis abundant (LEA) proteins are related to cellular dehydration tolerance. Most LEA proteins are predicted to have no stable secondary structure in solution, i.e., to be intrinsically disordered proteins (IDPs), but they may acquire α-helical structure upon drying. In the model plant Arabidopsis thaliana, the LEA proteins COR15A and COR15B are highly induced upon cold treatment and are necessary for the plants to attain full freezing tolerance. Freezing leads to increased intracellular crowding due to dehydration by extracellular ice crystals...
January 21, 2017: FEBS Journal
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