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Nature Chemical Biology

Fernando Villarreal, Luis E Contreras-Llano, Michael Chavez, Yunfeng Ding, Jinzhen Fan, Tingrui Pan, Cheemeng Tan
Assembly of recombinant multiprotein systems requires multiple culturing and purification steps that scale linearly with the number of constituent proteins. This problem is particularly pronounced in the preparation of the 34 proteins involved in transcription and translation systems, which are fundamental biochemistry tools for reconstitution of cellular pathways ex vivo. Here, we engineer synthetic microbial consortia consisting of between 15 and 34 Escherichia coli strains to assemble the 34 proteins in a single culturing, lysis, and purification procedure...
November 13, 2017: Nature Chemical Biology
Brittney A Beyer, Mingliang Fang, Benjamin Sadrian, J Rafael Montenegro-Burke, Warren C Plaisted, Bernard P C Kok, Enrique Saez, Toru Kondo, Gary Siuzdak, Luke L Lairson
Endogenous metabolites play essential roles in the regulation of cellular identity and activity. Here we have investigated the process of oligodendrocyte precursor cell (OPC) differentiation, a process that becomes limiting during progressive stages of demyelinating diseases, including multiple sclerosis, using mass-spectrometry-based metabolomics. Levels of taurine, an aminosulfonic acid possessing pleotropic biological activities and broad tissue distribution properties, were found to be significantly elevated (∼20-fold) during the course of oligodendrocyte differentiation and maturation...
November 13, 2017: Nature Chemical Biology
Owen S Skinner, Nicole A Haverland, Luca Fornelli, Rafael D Melani, Luis H F Do Vale, Henrique S Seckler, Peter F Doubleday, Luis F Schachner, Kristina Srzentić, Neil L Kelleher, Philip D Compton
Protein complexes exhibit great diversity in protein membership, post-translational modifications and noncovalent cofactors, enabling them to function as the actuators of many important biological processes. The exposition of these molecular features using current methods lacks either throughput or molecular specificity, ultimately limiting the use of protein complexes as direct analytical targets in a wide range of applications. Here, we apply native proteomics, enabled by a multistage tandem MS approach, to characterize 125 intact endogenous complexes and 217 distinct proteoforms derived from mouse heart and human cancer cell lines in discovery mode...
November 13, 2017: Nature Chemical Biology
Ryosuke Kojima, Leo Scheller, Martin Fussenegger
The ability to engineer custom cell-contact-sensing output devices into human nonimmune cells would be useful for extending the applicability of cell-based cancer therapies and for avoiding risks associated with engineered immune cells. Here we have developed a new class of synthetic T-cell receptor-like signal-transduction device that functions efficiently in human nonimmune cells and triggers release of output molecules specifically upon sensing contact with a target cell. This device employs an interleukin signaling cascade, whose OFF/ON switching is controlled by biophysical segregation of a transmembrane signal-inhibitory protein from the sensor cell-target cell interface...
November 13, 2017: Nature Chemical Biology
Ukrae Cho, Daniel P Riordan, Paulina Ciepla, Kiranmai S Kocherlakota, James K Chen, Pehr B Harbury
In principle, the millisecond emission lifetimes of lanthanide chelates should enable their ultrasensitive detection in biological systems by time-resolved optical microscopy. In practice, however, lanthanide imaging techniques have provided no better sensitivity than conventional fluorescence microscopy. Here, we identified three fundamental problems that have impeded lanthanide microscopy: low photon flux, inefficient excitation, and optics-derived background luminescence. We overcame these limitations with a new lanthanide imaging modality, transreflected illumination with luminescence resonance energy transfer (trLRET), which increases the time-integrated signal intensities of lanthanide lumiphores by 170-fold and the signal-to-background ratios by 75-fold...
November 6, 2017: Nature Chemical Biology
Jun Yan, Meng Bi, Allen K Bourdon, Abigail T Farmer, Po-Hsiang Wang, Olivia Molenda, Andrew T Quaile, Nannan Jiang, Yi Yang, Yongchao Yin, Burcu Şimşir, Shawn R Campagna, Elizabeth A Edwards, Frank E Löffler
Cobamides such as vitamin B12 are structurally conserved, cobalt-containing tetrapyrrole biomolecules that have essential biochemical functions in all domains of life. In organohalide respiration, a vital biological process for the global cycling of natural and anthropogenic organohalogens, cobamides are the requisite prosthetic groups for carbon-halogen bond-cleaving reductive dehalogenases. This study reports the biosynthesis of a new cobamide with unsubstituted purine as the lower base and assigns unsubstituted purine a biological function by demonstrating that Coα-purinyl-cobamide (purinyl-Cba) is the native prosthetic group in catalytically active tetrachloroethene reductive dehalogenases of Desulfitobacterium hafniense...
November 6, 2017: Nature Chemical Biology
David Sychantha, Dustin J Little, Robert N Chapman, Geert-Jan Boons, Howard Robinson, P Lynne Howell, Anthony J Clarke
O-Acetylation of the secondary cell wall polysaccharides (SCWP) of the Bacillus cereus group of pathogens, which includes Bacillus anthracis, is essential for the proper attachment of surface-layer (S-layer) proteins to their cell walls. Using a variety of pseudosubstrates and a chemically synthesized analog of SCWP, we report here the identification of PatB1 as a SCWP O-acetyltransferase in Bacillus cereus. Additionally, we report the crystal structure of PatB1, which provides detailed insights into the mechanism of this enzyme and defines a novel subfamily of the SGNH family of esterases and lipases...
October 30, 2017: Nature Chemical Biology
Zhaowei Chen, Jinqiang Wang, Wujin Sun, Edikan Archibong, Anna R Kahkoska, Xudong Zhang, Yue Lu, Frances S Ligler, John B Buse, Zhen Gu
Generating artificial pancreatic beta cells by using synthetic materials to mimic glucose-responsive insulin secretion in a robust manner holds promise for improving clinical outcomes in people with diabetes. Here, we describe the construction of artificial beta cells (AβCs) with a multicompartmental 'vesicles-in-vesicle' superstructure equipped with a glucose-metabolism system and membrane-fusion machinery. Through a sequential cascade of glucose uptake, enzymatic oxidation and proton efflux, the AβCs can effectively distinguish between high and normal glucose levels...
October 30, 2017: Nature Chemical Biology
Yi Qu, Jan Roger Olsen, Xing Yuan, Phil F Cheng, Mitchell P Levesque, Karl A Brokstad, Paul S Hoffman, Anne Margrete Oyan, Weidong Zhang, Karl-Henning Kalland, Xisong Ke
Wnt (wingless)/β-catenin signaling is critical for tumor progression and is frequently activated in colorectal cancer as a result of the mutation of adenomatous polyposis coli (APC); however, therapeutic agents targeting this pathway for clinical use are lacking. Here we report that nitazoxanide (NTZ), a clinically approved antiparasitic drug, efficiently inhibits Wnt signaling independent of APC. Using chemoproteomic approaches, we have identified peptidyl arginine deiminase 2 (PAD2) as the functional target of NTZ in Wnt inhibition...
October 30, 2017: Nature Chemical Biology
James A Davey, Adam M Damry, Natalie K Goto, Roberto A Chica
Proteins are intrinsically dynamic molecules that can exchange between multiple conformational states, enabling them to carry out complex molecular processes with extreme precision and efficiency. Attempts to design novel proteins with tailored functions have mostly failed to yield efficiencies matching those found in nature because standard methods do not allow the design of exchange between necessary conformational states on a functionally relevant timescale. Here we developed a broadly applicable computational method to engineer protein dynamics that we term meta-multistate design...
October 23, 2017: Nature Chemical Biology
Colleen R Reczek, Kıvanç Birsoy, Hyewon Kong, Inmaculada Martínez-Reyes, Tim Wang, Peng Gao, David M Sabatini, Navdeep S Chandel
Paraquat, a herbicide linked to Parkinson's disease, generates reactive oxygen species (ROS), which causes cell death. Because the source of paraquat-induced ROS production remains unknown, we conducted a CRISPR-based positive-selection screen to identify metabolic genes essential for paraquat-induced cell death. Our screen uncovered three genes, POR (cytochrome P450 oxidoreductase), ATP7A (copper transporter), and SLC45A4 (sucrose transporter), required for paraquat-induced cell death. Furthermore, our results revealed POR as the source of paraquat-induced ROS production...
October 23, 2017: Nature Chemical Biology
Chia-Wei Hu, Matthew Worth, Dacheng Fan, Baobin Li, Hao Li, Lei Lu, Xiaofang Zhong, Ziqing Lin, Liming Wei, Ying Ge, Lingjun Li, Jiaoyang Jiang
O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is an essential human glycosyltransferase that adds O-GlcNAc modifications to numerous proteins. However, little is known about the mechanism with which OGT recognizes various protein substrates. Here we report on GlcNAc electrophilic probes (GEPs) to expedite the characterization of OGT-substrate recognition. Data from mass spectrometry, X-ray crystallization, and biochemical and radiolabeled kinetic assays support the application of GEPs to rapidly report the impacts of OGT mutations on protein substrate or sugar binding and to discover OGT residues crucial for protein recognition...
October 23, 2017: Nature Chemical Biology
Tateki Suzuki, Corwin Miller, Li-Tao Guo, Joanne M L Ho, David I Bryson, Yane-Shih Wang, David R Liu, Dieter Söll
Pyrrolysyl-tRNA synthetase (PylRS) is a major tool in genetic code expansion using noncanonical amino acids, yet its structure and function are not completely understood. Here we describe the crystal structure of the previously uncharacterized essential N-terminal domain of this unique enzyme in complex with tRNA(Pyl). This structure explains why PylRS remains orthogonal in a broad range of organisms, from bacteria to humans. The structure also illustrates why tRNA(Pyl) recognition by PylRS is anticodon independent: the anticodon does not contact the enzyme...
October 16, 2017: Nature Chemical Biology
Marcus Braun, Zdenek Lansky, Agata Szuba, Friedrich W Schwarz, Aniruddha Mitra, Mengfei Gao, Annemarie Lüdecke, Pieter Rein Ten Wolde, Stefan Diez
Microtubule-crosslinking motor proteins, which slide antiparallel microtubules, are required for the remodeling of microtubule networks. Hitherto, all microtubule-crosslinking motors have been shown to slide microtubules at a constant velocity until no overlap remains between them, leading to the breakdown of the initial microtubule geometry. Here, we show in vitro that the sliding velocity of microtubules, driven by human kinesin-14 HSET, decreases when microtubules start to slide apart, resulting in the maintenance of finite-length microtubule overlaps...
October 16, 2017: Nature Chemical Biology
David I Bryson, Chenguang Fan, Li-Tao Guo, Corwin Miller, Dieter Söll, David R Liu
Directed evolution of orthogonal aminoacyl-tRNA synthetases (AARSs) enables site-specific installation of noncanonical amino acids (ncAAs) into proteins. Traditional evolution techniques typically produce AARSs with greatly reduced activity and selectivity compared to their wild-type counterparts. We designed phage-assisted continuous evolution (PACE) selections to rapidly produce highly active and selective orthogonal AARSs through hundreds of generations of evolution. PACE of a chimeric Methanosarcina spp...
October 16, 2017: Nature Chemical Biology
Brent M Kuenzi, Lily L Remsing Rix, Paul A Stewart, Bin Fang, Fumi Kinose, Annamarie T Bryant, Theresa A Boyle, John M Koomen, Eric B Haura, Uwe Rix
Targeted drugs are effective when they directly inhibit strong disease drivers, but only a small fraction of diseases feature defined actionable drivers. Alternatively, network-based approaches can uncover new therapeutic opportunities. Applying an integrated phenotypic screening, chemical and phosphoproteomics strategy, here we describe the anaplastic lymphoma kinase (ALK) inhibitor ceritinib as having activity across several ALK-negative lung cancer cell lines and identify new targets and network-wide signaling effects...
October 9, 2017: Nature Chemical Biology
Ireos Filipuzzi, Janos Steffen, Mitchel Germain, Laetitia Goepfert, Michael A Conti, Christoph Potting, Raffaele Cerino, Martin Pfeifer, Philipp Krastel, Dominic Hoepfner, Julie Bastien, Carla M Koehler, Stephen B Helliwell
Tim17 and Tim23 are the main subunits of the TIM23 complex, one of the two major essential mitochondrial inner-membrane protein translocon machineries (TIMs). No chemical probes that specifically inhibit TIM23-dependent protein import were known to exist. Here we show that the natural product stendomycin, produced by Streptomyces hygroscopicus, is a potent and specific inhibitor of the TIM23 complex in yeast and mammalian cells. Furthermore, stendomycin-mediated blockage of the TIM23 complex does not alter normal processing of the major regulatory mitophagy kinase PINK1, but TIM23 is required to stabilize PINK1 on the outside of mitochondria to initiate mitophagy upon membrane depolarization...
October 9, 2017: Nature Chemical Biology
Drew M Dolino, Sudeshna Chatterjee, David M MacLean, Charlotte Flatebo, Logan D C Bishop, Sana A Shaikh, Christy F Landes, Vasanthi Jayaraman
N-Methyl-D-aspartate (NMDA) receptors are the main calcium-permeable excitatory receptors in the mammalian central nervous system. The NMDA receptor gating is complex, exhibiting multiple closed, open, and desensitized states; however, central questions regarding the conformations and energetics of the transmembrane domains as they relate to the gating states are still unanswered. Here, using single-molecule Förster resonance energy transfer (smFRET), we map the energy landscape of the first transmembrane segment of the Rattus norvegicus NMDA receptor under resting and various liganded conditions...
October 9, 2017: Nature Chemical Biology
Yirui Guo, Daniel L M Suess, Mark A Herzik, Anthony T Iavarone, R David Britt, Michael A Marletta
The binding of nitric oxide (NO) to the heme cofactor of heme-nitric oxide/oxygen binding (H-NOX) proteins can lead to the dissociation of the heme-ligating histidine residue and yield a five-coordinate nitrosyl complex, an important step for NO-dependent signaling. In the five-coordinate nitrosyl complex, NO can reside on either the distal or proximal side of the heme, which could have a profound influence over the lifetime of the in vivo signal. To investigate this central molecular question, we characterized the Shewanella oneidensis H-NOX (So H-NOX)-NO complex biophysically under limiting and excess NO conditions...
October 2, 2017: Nature Chemical Biology
Ellen L Weisberg, Nathan J Schauer, Jing Yang, Ilaria Lamberto, Laura Doherty, Shruti Bhatt, Atsushi Nonami, Chengcheng Meng, Anthony Letai, Renee Wright, Hong Tiv, Prafulla C Gokhale, Maria Stella Ritorto, Virginia De Cesare, Matthias Trost, Alexandra Christodoulou, Amanda Christie, David M Weinstock, Sophia Adamia, Richard Stone, Dharminder Chauhan, Kenneth C Anderson, Hyuk-Soo Seo, Sirano Dhe-Paganon, Martin Sattler, Nathanael S Gray, James D Griffin, Sara J Buhrlage
Oncogenic forms of the kinase FLT3 are important therapeutic targets in acute myeloid leukemia (AML); however, clinical responses to small-molecule kinase inhibitors are short-lived as a result of the rapid emergence of resistance due to point mutations or compensatory increases in FLT3 expression. We sought to develop a complementary pharmacological approach whereby proteasome-mediated FLT3 degradation could be promoted by inhibitors of the deubiquitinating enzymes (DUBs) responsible for cleaving ubiquitin from FLT3...
October 2, 2017: Nature Chemical Biology
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