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Cell Chemical Biology

Li Wang, John A Wrobel, Ling Xie, DongXu Li, Giada Zurlo, Huali Shen, Pengyuan Yang, Zefeng Wang, Yibing Peng, Harsha P Gunawardena, Qing Zhang, Xian Chen
To discriminate the patient subpopulations with different clinical outcomes within each breast cancer (BC) subtype, we introduce a robust, clinical-practical, activity-based proteogenomic method that identifies, in their oncogenically active states, candidate biomarker genes bearing patient-specific transcriptomic/genomic alterations of prognostic value. First, we used the intronic splicing enhancer (ISE) probes to sort ISE-interacting trans-acting protein factors (trans-interactome) directly from a tumor tissue for subsequent mass spectrometry characterization...
February 27, 2018: Cell Chemical Biology
Jun Li, Hui-Chen Hsu, John D Mountz, John G Allen
Fucosylation is a biological process broadly observed in vertebrates, invertebrates, plants, bacteria, and fungi. Fucose moieties on cell-surface glycans are increasingly recognized as critical to many cell-cell interaction and signaling processes. One of the characteristic roles of fucose is its regulation of selectin-dependent leukocyte adhesion that has been well studied over the last two decades. Recent studies of fucose in immune cell development and function regulation have significantly expanded the contemporary understanding of fucosylation...
February 24, 2018: Cell Chemical Biology
Mario Mardirossian, Natacha Pérébaskine, Monica Benincasa, Stefano Gambato, Sven Hofmann, Paul Huter, Claudia Müller, Kai Hilpert, C Axel Innis, Alessandro Tossi, Daniel N Wilson
Proline-rich antimicrobial peptides (PrAMPs) internalize into susceptible bacteria using specific transporters and interfere with protein synthesis and folding. To date, mammalian PrAMPs have so far been identified only in artiodactyls. Since cetaceans are co-phyletic with artiodactyls, we mined the genome of the bottlenose dolphin Tursiops truncatus, leading to the identification of two PrAMPs, Tur1A and Tur1B. Tur1A, which is orthologous to the bovine PrAMP Bac7, is internalized into Escherichia coli, without damaging the membranes, using the inner membrane transporters SbmA and YjiL/MdM...
February 22, 2018: Cell Chemical Biology
Seema Irani, Nathchar Naowarojna, Yang Tang, Karan R Kathuria, Shu Wang, Anxhela Dhembi, Norman Lee, Wupeng Yan, Huijue Lyu, Catherine E Costello, Pinghua Liu, Yan Jessie Zhang
Sulfur incorporation in the biosynthesis of ergothioneine, a histidine thiol derivative, differs from other well-characterized transsulfurations. A combination of a mononuclear non-heme iron enzyme-catalyzed oxidative C-S bond formation and a subsequent pyridoxal 5'-phosphate (PLP)-mediated C-S lyase reaction leads to the net transfer of a sulfur atom from a cysteine to a histidine. In this study, we structurally and mechanistically characterized a PLP-dependent C-S lyase Egt2, which mediates the sulfoxide C-S bond cleavage in ergothioneine biosynthesis...
February 22, 2018: Cell Chemical Biology
Kohei Omachi, Misato Kamura, Keisuke Teramoto, Haruka Kojima, Tsubasa Yokota, Shota Kaseda, Jun Kuwazuru, Ryosuke Fukuda, Kosuke Koyama, Shingo Matsuyama, Keishi Motomura, Tsuyoshi Shuto, Mary Ann Suico, Hirofumi Kai
Alport syndrome is a hereditary glomerular disease caused by mutation in type IV collagen α3-α5 chains (α3-α5(IV)), which disrupts trimerization, leading to glomerular basement membrane degeneration. Correcting the trimerization of α3/α4/α5 chain is a feasible therapeutic approach, but is hindered by lack of information on the regulation of intracellular α(IV) chain and the absence of high-throughput screening (HTS) platforms to assess α345(IV) trimer formation. Here, we developed sets of split NanoLuc-fusion α345(IV) proteins to monitor α345(IV) trimerization of wild-type and clinically associated mutant α5(IV)...
February 21, 2018: Cell Chemical Biology
Daniela Buonvicino, Francesca Mazzola, Federica Zamporlini, Francesco Resta, Giuseppe Ranieri, Emidio Camaioni, Mirko Muzzi, Riccardo Zecchi, Giuseppe Pieraccini, Christian Dölle, Massimo Calamante, Gianluca Bartolucci, Mathias Ziegler, Barbara Stecca, Nadia Raffaelli, Alberto Chiarugi
Interest in the modulation of nicotinamide adenine dinucleotide (NAD) metabolome is gaining great momentum because of its therapeutic potential in different human disorders. Suppression of nicotinamide salvage by nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, however, gave inconclusive results in neoplastic patients because several metabolic routes circumvent the enzymatic block converging directly on nicotinamide mononucleotide adenylyl transferases (NMNATs) for NAD synthesis. Unfortunately, NMNAT inhibitors have not been identified...
February 19, 2018: Cell Chemical Biology
Jaak Simm, Günter Klambauer, Adam Arany, Marvin Steijaert, Jörg Kurt Wegner, Emmanuel Gustin, Vladimir Chupakhin, Yolanda T Chong, Jorge Vialard, Peter Buijnsters, Ingrid Velter, Alexander Vapirev, Shantanu Singh, Anne E Carpenter, Roel Wuyts, Sepp Hochreiter, Yves Moreau, Hugo Ceulemans
In both academia and the pharmaceutical industry, large-scale assays for drug discovery are expensive and often impractical, particularly for the increasingly important physiologically relevant model systems that require primary cells, organoids, whole organisms, or expensive or rare reagents. We hypothesized that data from a single high-throughput imaging assay can be repurposed to predict the biological activity of compounds in other assays, even those targeting alternate pathways or biological processes...
February 16, 2018: Cell Chemical Biology
John M Hatcher, Guowei Wu, Chuyue Zeng, Jie Zhu, Fan Meng, Sherrina Patel, Wenqiu Wang, Scott B Ficarro, Alan L Leggett, Chelsea E Powell, Jarrod A Marto, Kang Zhang, Jacky Chi Ki Ngo, Xiang-Dong Fu, Tinghu Zhang, Nathanael S Gray
The SRPK family of kinases regulates pre-mRNA splicing by phosphorylating serine/arginine (SR)-rich splicing factors, signals splicing control in response to extracellular stimuli, and contributes to tumorigenesis, suggesting that these splicing kinases are potential therapeutic targets. Here, we report the development of the first irreversible SRPK inhibitor, SRPKIN-1, which is also the first kinase inhibitor that forms a covalent bond with a tyrosine phenol group in the ATP-binding pocket. Kinome-wide profiling demonstrates its selectivity for SRPK1/2, and SRPKIN-1 attenuates SR protein phosphorylation at submicromolar concentrations...
February 14, 2018: Cell Chemical Biology
Mark C Anderson, Thibault Chaze, Yves-Marie Coïc, Louise Injarabian, Friederike Jonsson, Naelle Lombion, Dorothée Selimoglu-Buet, Judith Souphron, Caroline Ridley, Pascale Vonaesch, Bruno Baron, Ellen T Arena, Jean-Yves Tinevez, Giulia Nigro, Katharina Nothelfer, Eric Solary, Valérie Lapierre, Thierry Lazure, Mariette Matondo, David Thornton, Philippe J Sansonetti, Françoise Baleux, Benoit S Marteyn
Neutrophils represent the most abundant immune cells recruited to inflamed tissues. A lack of dedicated tools has hampered their detection and study. We show that a synthesized peptide, MUB40 , binds to lactoferrin, the most abundant protein stored in neutrophil-specific and tertiary granules. Lactoferrin is specifically produced by neutrophils among other leukocytes, making MUB40 a specific neutrophil marker. Naive mammalian neutrophils (human, guinea pig, mouse, rabbit) were labeled by fluorescent MUB40 conjugates (-Cy5, Dylight405)...
February 13, 2018: Cell Chemical Biology
Sara H Rouhanifard, Aime Lopez Aguilar, Lu Meng, Kelley W Moremen, Peng Wu
At the base of the intestinal crypt, long-lived Lgr5+ stem cells are intercalated by Paneth cells that provide essential niche signals for stem cell maintenance. This unique epithelial anatomy makes the intestinal crypt one of the most accessible models for the study of adult stem cell biology. The glycosylation patterns of this compartment are poorly characterized, and the impact of glycans on stem cell differentiation remains largely unexplored. We find that Paneth cells, but not Lgr5+ stem cells, express abundant terminal N-acetyllactosamine (LacNAc)...
February 1, 2018: Cell Chemical Biology
Hyun Tae Kim, Byeong Kwan Na, Jiwoung Chung, Sulhee Kim, Sool Ki Kwon, Hyunju Cha, Jonghyeon Son, Joong Myung Cho, Kwang Yeon Hwang
Kynurenine 3-monooxygenase (KMO) inhibitors have been developed for the treatment of neurodegenerative disorders. The mechanisms of flavin reduction and hydrogen peroxide production by KMO inhibitors are unknown. Herein, we report the structure of human KMO and crystal structures of Saccharomyces cerevisiae (sc) and Pseudomonas fluorescens (pf) KMO with Ro 61-8048. Proton transfer in the hydrogen bond network triggers flavin reduction in p-hydroxybenzoate hydroxylase, but the mechanism triggering flavin reduction in KMO is different...
February 1, 2018: Cell Chemical Biology
Daria Ezeriņa, Yoko Takano, Kenjiro Hanaoka, Yasuteru Urano, Tobias P Dick
The cysteine prodrug N-acetyl cysteine (NAC) is widely used as a pharmacological antioxidant and cytoprotectant. It has been reported to lower endogenous oxidant levels and to protect cells against a wide range of pro-oxidative insults. As NAC itself is a poor scavenger of oxidants, the molecular mechanisms behind the antioxidative effects of NAC have remained uncertain. Here we show that NAC-derived cysteine is desulfurated to generate hydrogen sulfide, which in turn is oxidized to sulfane sulfur species, predominantly within mitochondria...
January 29, 2018: Cell Chemical Biology
Charlotte A James, Krystle K Q Yu, Martine Gilleron, Jacques Prandi, Vijayendar R Yedulla, Zuzanna Z Moleda, Eleonora Diamanti, Momin Khan, Varinder K Aggarwal, Josephine F Reijneveld, Peter Reinink, Stefanie Lenz, Ryan O Emerson, Thomas J Scriba, Michael N T Souter, Dale I Godfrey, Daniel G Pellicci, D Branch Moody, Adriaan J Minnaard, Chetan Seshadri, Ildiko Van Rhijn
Mycobacterial cell wall lipids bind the conserved CD1 family of antigen-presenting molecules and activate T cells via their T cell receptors (TCRs). Sulfoglycolipids (SGLs) are uniquely synthesized by Mycobacterium tuberculosis, but tools to study SGL-specific T cells in humans are lacking. We designed a novel hybrid synthesis of a naturally occurring SGL, generated CD1b tetramers loaded with natural or synthetic SGL analogs, and studied the molecular requirements for TCR binding and T cell activation...
January 29, 2018: Cell Chemical Biology
Douglas Ganini, Janine H Santos, Marcelo G Bonini, Ronald P Mason
Superoxide radical anion (O2⋅‒) and other reactive oxygen species are constantly produced during respiration. In mitochondria, the dismutation of O2⋅‒ is accelerated by the mitochondrial superoxide dismutase 2 (SOD2), an enzyme that has been traditionally associated with antioxidant protection. However, increases in SOD2 expression promote oxidative stress, indicating that there may be a prooxidant role for SOD2. Here we show that SOD2, which normally binds manganese, can incorporate iron and generate an alternative isoform with peroxidase activity...
January 26, 2018: Cell Chemical Biology
Kalinka Koteva, Georgina Cox, Jayne K Kelso, Matthew D Surette, Haley L Zubyk, Linda Ejim, Peter Stogios, Alexei Savchenko, Dan Sørensen, Gerard D Wright
Rifamycin monooxygenases (Rox) are present in a variety of environmental bacteria and are associated with decomposition of the clinically utilized antibiotic rifampin. Here we report the structure and function of a drug-inducible rox gene from Streptomyces venezuelae, which encodes a class A flavoprotein monooxygenase that inactivates a broad range of rifamycin antibiotics. Our findings describe a mechanism of rifamycin inactivation initiated by monooxygenation of the 2-position of the naphthyl group, which subsequently results in ring opening and linearization of the antibiotic...
January 26, 2018: Cell Chemical Biology
Susanne Höing, Ting-Yu Yeh, Matthias Baumann, Nancy E Martinez, Peter Habenberger, Lea Kremer, Hannes C A Drexler, Philipp Küchler, Peter Reinhardt, Axel Choidas, Mia-Lisa Zischinsky, Gunther Zischinsky, Swaran Nandini, Aaron P Ledray, Stephanie A Ketcham, Lydia Reinhardt, Masin Abo-Rady, Michael Glatza, Stephen J King, Peter Nussbaumer, Slava Ziegler, Bert Klebl, Trina A Schroer, Hans R Schöler, Herbert Waldmann, Jared Sterneckert
Aberrant hedgehog (Hh) signaling contributes to the pathogenesis of multiple cancers. Available inhibitors target Smoothened (Smo), which can acquire mutations causing drug resistance. Thus, compounds that inhibit Hh signaling downstream of Smo are urgently needed. We identified dynarrestin, a novel inhibitor of cytoplasmic dyneins 1 and 2. Dynarrestin acts reversibly to inhibit cytoplasmic dynein 1-dependent microtubule binding and motility in vitro without affecting ATP hydrolysis. It rapidly and reversibly inhibits endosome movement in living cells and perturbs mitosis by inducing spindle misorientation and pseudoprometaphase delay...
January 26, 2018: Cell Chemical Biology
Iva Hánová, Jiří Brynda, Radka Houštecká, Nawsad Alam, Daniel Sojka, Petr Kopáček, Lucie Marešová, Jiří Vondrášek, Martin Horn, Ora Schueler-Furman, Michael Mareš
Pepsin-family aspartic peptidases are biosynthesized as inactive zymogens in which the propeptide blocks the active site until its proteolytic removal upon enzyme activation. Here, we describe a novel dual regulatory function for the propeptide using a set of crystal structures of the parasite cathepsin D IrCD1. In the IrCD1 zymogen, intramolecular autoinhibition by the intact propeptide is mediated by an evolutionarily conserved exosite on the enzyme core. After activation, the mature enzyme employs the same exosite to rebind a small fragment derived from the cleaved propeptide...
January 26, 2018: Cell Chemical Biology
Marian C Okondo, Sahana D Rao, Cornelius Y Taabazuing, Ashley J Chui, Sarah E Poplawski, Darren C Johnson, Daniel A Bachovchin
Val-boroPro (PT-100, Talabostat) induces powerful anti-tumor immune responses in syngeneic cancer models, but its mechanism of action has not yet been established. Val-boroPro is a non-selective inhibitor of post-proline-cleaving serine proteases, and the inhibition of the highly related cytosolic serine proteases Dpp8 and Dpp9 (Dpp8/9) by Val-boroPro was recently demonstrated to trigger an immunostimulatory form of programmed cell death known as pyroptosis selectively in monocytes and macrophages. Here we show that Dpp8/9 inhibition activates the inflammasome sensor protein Nlrp1b, which in turn activates pro-caspase-1 to mediate pyroptosis...
January 26, 2018: Cell Chemical Biology
Praopim Limsakul, Qin Peng, Yiqian Wu, Molly E Allen, Jing Liang, Albert G Remacle, Tyler Lopez, Xin Ge, Brian K Kay, Huimin Zhao, Alex Y Strongin, Xiang-Lei Yang, Shaoying Lu, Yingxiao Wang
Monitoring enzymatic activities at the cell surface is challenging due to the poor efficiency of transport and membrane integration of fluorescence resonance energy transfer (FRET)-based biosensors. Therefore, we developed a hybrid biosensor with separate donor and acceptor that assemble in situ. The directed evolution and sequence-function analysis technologies were integrated to engineer a monobody variant (PEbody) that binds to R-phycoerythrin (R-PE) dye. PEbody was used for visualizing the dynamic formation/separation of intercellular junctions...
January 26, 2018: Cell Chemical Biology
Tony Velkov, Alejandra Gallardo-Godoy, James D Swarbrick, Mark A T Blaskovich, Alysha G Elliott, Meiling Han, Philip E Thompson, Kade D Roberts, Johnny X Huang, Bernd Becker, Mark S Butler, Lawrence H Lash, Sónia Troeira Henriques, Roger L Nation, Sivashangarie Sivanesan, Marc-Antoine Sani, Frances Separovic, Haydyn Mertens, Dieter Bulach, Torsten Seemann, Jeremy Owen, Jian Li, Matthew A Cooper
Resistance to the last-resort antibiotic colistin is now widespread and new therapeutics are urgently required. We report the first in toto chemical synthesis and pre-clinical evaluation of octapeptins, a class of lipopeptides structurally related to colistin. The octapeptin biosynthetic cluster consisted of three non-ribosomal peptide synthetases (OctA, OctB, and OctC) that produced an amphiphilic antibiotic, octapeptin C4, which was shown to bind to and depolarize membranes. While active against multi-drug resistant (MDR) strains in vitro, octapeptin C4 displayed poor in vivo efficacy, most likely due to high plasma protein binding...
January 23, 2018: Cell Chemical Biology
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