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Cell Chemical Biology

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https://www.readbyqxmd.com/read/28343940/lithocholic-acid-hydroxyamide-destabilizes-cyclin-d1-and-induces-g0-g1-arrest-by-inhibiting-deubiquitinase-usp2a
#1
Katarzyna Magiera, Marcin Tomala, Katarzyna Kubica, Virginia De Cesare, Matthias Trost, Bartosz J Zieba, Neli Kachamakova-Trojanowska, Marcin Les, Grzegorz Dubin, Tad A Holak, Lukasz Skalniak
USP2a is a deubiquitinase responsible for stabilization of cyclin D1, a crucial regulator of cell-cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent LCA derivative, LCA hydroxyamide (LCAHA), inhibits USP2a, leading to a significant Akt/GSK3β-independent destabilization of cyclin D1, but does not change the expression of p27. This leads to the defects in cell-cycle progression...
March 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28330605/polyubiquitin-photoactivatable-crosslinking-reagents-for-mapping-ubiquitin-interactome-identify-rpn1-as-a-proteasome-ubiquitin-associating-subunit
#2
Michal Chojnacki, Wissam Mansour, Dharjath S Hameed, Rajesh K Singh, Farid El Oualid, Rina Rosenzweig, Mark A Nakasone, Zanlin Yu, Fabian Glaser, Lewis E Kay, David Fushman, Huib Ovaa, Michael H Glickman
Ubiquitin (Ub) signaling is a diverse group of processes controlled by covalent attachment of small protein Ub and polyUb chains to a range of cellular protein targets. The best documented Ub signaling pathway is the one that delivers polyUb proteins to the 26S proteasome for degradation. However, studies of molecular interactions involved in this process have been hampered by the transient and hydrophobic nature of these interactions and the lack of tools to study them. Here, we develop Ub-phototrap (Ub(PT)), a synthetic Ub variant containing a photoactivatable crosslinking side chain...
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28330604/stable-and-potent-selenomab-drug-conjugates
#3
Xiuling Li, Christopher G Nelson, Rajesh R Nair, Lori Hazlehurst, Tina Moroni, Pablo Martinez-Acedo, Alex R Nanna, David Hymel, Terrence R Burke, Christoph Rader
Selenomabs are engineered monoclonal antibodies with one or more translationally incorporated selenocysteine residues. The unique reactivity of the selenol group of selenocysteine permits site-specific conjugation of drugs. Compared with other natural and unnatural amino acid and carbohydrate residues that have been used for the generation of site-specific antibody-drug conjugates, selenocysteine is particularly reactive, permitting fast, single-step, and efficient reactions under near physiological conditions...
March 9, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28163016/discovering-targets-of-non-enzymatic-acylation-by-thioester-reactivity-profiling
#4
Rhushikesh A Kulkarni, Andrew J Worth, Thomas T Zengeya, Jonathan H Shrimp, Julie M Garlick, Allison M Roberts, David C Montgomery, Carole Sourbier, Benjamin K Gibbs, Clementina Mesaros, Yien Che Tsai, Sudipto Das, King C Chan, Ming Zhou, Thorkell Andresson, Allan M Weissman, W Marston Linehan, Ian A Blair, Nathaniel W Snyder, Jordan L Meier
Non-enzymatic protein modification driven by thioester reactivity is thought to play a major role in the establishment of cellular lysine acylation. However, the specific protein targets of this process are largely unknown. Here we report an experimental strategy to investigate non-enzymatic acylation in cells. Specifically, we develop a chemoproteomic method that separates thioester reactivity from enzymatic utilization, allowing selective enrichment of non-enzymatic acylation targets. Applying this method to cancer cell lines identifies numerous candidate targets of non-enzymatic acylation, including several enzymes in lower glycolysis...
January 31, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28132895/cbp-p300-bromodomain-mediates-amyloid-formation
#5
Daiqing Liao
Bromodomains are protein domains that serve as "readers" of acetylated lysine marks and mediate DNA-templated processes. In this issue of Cell Chemical Biology, Olzscha et al. (2017) report that the CBP/p300 bromodomains mediate the formation of amyloid-like aggregates and that inhibitors specific to these bromodomains reduce the degree of protein aggregation and mitigate HDAC inhibitor-induced cytotoxicity.
January 26, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28132894/vitamin-d-metabolite-25-hydroxyvitamin-d-regulates-lipid-metabolism-by-inducing-degradation-of-srebp-scap
#6
Lisa Asano, Mizuki Watanabe, Yuta Ryoden, Kousuke Usuda, Takuya Yamaguchi, Bilon Khambu, Megumi Takashima, Shin-Ichi Sato, Juro Sakai, Kazuo Nagasawa, Motonari Uesugi
Sterol regulatory element-binding proteins (SREBPs) are transcription factors that control lipid homeostasis. SREBP activation is regulated by a negative feedback loop in which sterols bind to SREBP cleavage-activating protein (SCAP), an escort protein essential for SREBP activation, or to insulin-induced genes (Insigs) (endoplasmic reticulum [ER] anchor proteins), sequestering the SREBP-SCAP-Insig complex in the ER. We screened a chemical library of endogenous molecules and identified 25-hydroxyvitamin D (25OHD) as an inhibitor of SREBP activation...
January 23, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28132892/mapping-proteome-wide-targets-of-glyphosate-in-mice
#7
Breanna Ford, Leslie A Bateman, Leilani Gutierrez-Palominos, Robin Park, Daniel K Nomura
Glyphosate, the active ingredient in the herbicide Roundup, is one of the most widely used pesticides in agriculture and home garden use. Whether glyphosate causes any mammalian toxicity remains highly controversial. While many studies have associated glyphosate with numerous adverse health effects, the mechanisms underlying glyphosate toxicity in mammals remain poorly understood. Here, we used activity-based protein profiling to map glyphosate targets in mice. We show that glyphosate at high doses can be metabolized in vivo to reactive metabolites such as glyoxylate and react with cysteines across many proteins in mouse liver...
January 19, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28111099/talaromyces-marneffei-mp1p-is-a-virulence-factor-that-binds-and-sequesters-a-key-proinflammatory-lipid-to-dampen-host-innate-immune-response
#8
Kong-Hung Sze, Wai-Hei Lam, Hongmin Zhang, Yi-Hong Ke, Man-Kit Tse, Patrick C Y Woo, Susanna K P Lau, Candy C Y Lau, Jian-Piao Cai, Edward T K Tung, Raymond K C Lo, Simin Xu, Richard Y T Kao, Quan Hao, Kwok-Yung Yuen
Talaromyces (Penicillium) marneffei is one of the leading causes of systemic mycosis in immunosuppressed or AIDS patients in Southeast Asia. How this intracellular pathogen evades the host immune defense remains unclear. We provide evidence that T. marneffei depletes levels of a key proinflammatory lipid mediator arachidonic acid (AA) to evade the host innate immune defense. Mechanistically, an abundant secretory mannoprotein Mp1p, shown previously to be a virulence factor, does so by binding AA with high affinity via a long hydrophobic central cavity found in the LBD2 domain...
January 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28111098/carbon-sources-tune-antibiotic-susceptibility-in-pseudomonas-aeruginosa-via-tricarboxylic-acid-cycle-control
#9
Sylvain Meylan, Caroline B M Porter, Jason H Yang, Peter Belenky, Arnaud Gutierrez, Michael A Lobritz, Jihye Park, Sun H Kim, Samuel M Moskowitz, James J Collins
Metabolically dormant bacteria present a critical challenge to effective antimicrobial therapy because these bacteria are genetically susceptible to antibiotic treatment but phenotypically tolerant. Such tolerance has been attributed to impaired drug uptake, which can be reversed by metabolic stimulation. Here, we evaluate the effects of central carbon metabolite stimulations on aminoglycoside sensitivity in the pathogen Pseudomonas aeruginosa. We identify fumarate as a tobramycin potentiator that activates cellular respiration and generates a proton motive force by stimulating the tricarboxylic acid (TCA) cycle...
January 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28111097/an-unusual-protector-prot%C3%A3-g%C3%A3-strategy-for-the-biosynthesis-of-purine-nucleoside-antibiotics
#10
Pan Wu, Dan Wan, Gudan Xu, Gui Wang, Hongmin Ma, Tingting Wang, Yaojie Gao, Jianzhao Qi, Xiaoxia Chen, Jian Zhu, Yong-Quan Li, Zixin Deng, Wenqing Chen
Pentostatin (PTN, deoxycoformycin) and arabinofuranosyladenine (Ara-A, vidarabine) are purine nucleoside antibiotics used clinically to treat hematological cancers and human DNA virus infections, respectively. PTN has a 1,3-diazepine ring, and Ara-A is an adenosine analog with an intriguing epimerization at the C-2' hydroxyl group. However, the logic underlying the biosynthesis of these interesting molecules has long remained elusive. Here, we report that the biosynthesis of PTN and Ara-A employs an unusual protector-protégé strategy...
January 12, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28089757/disorazoles-block-group-a-streptococcal-invasion-into-epithelial-cells-via-interference-with-the-host-factor-ezrin
#11
Katharina Rox, Manfred Rohde, Gursharan Singh Chhatwal, Rolf Müller
Bacterial pathogens use invasion into human cells as a strategy to escape not only the host's immune response, but also anti-bacterial treatment. This often leads to persistence and enables reinitiation of the infection process at a later time point. Here, we show that a family of myxobacterial metabolites, disorazoles, block invasion of group A Streptococcus (GAS) into human epithelial cells. Mechanistically, disorazoles target ezrin, a host protein involved in linking microfilaments to the membrane, and affect invasion most likely by interfering with dynamic phosphorylation of ezrin...
January 5, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28306501/mapping-new-residents-of-the-mitochondrial-nucleoid
#12
Laura Trinkle-Mulcahy
In this issue of Cell Chemical Biology, Han et al. (2017) used a powerful combination of quantitative ratiometric mass spectrometry with APEX peroxidase-catalyzed proximity biotinylation to selectively highlight proteins associated with mitochondrial DNA above the background of contaminants and matrix proteins. In addition to identifying novel nucleoid factors, this study extends the APEX strategy to the proteomic mapping of non-membrane-bound multiprotein complexes.
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28306500/catching-sirtuin-2-intermediates-one-structure-at-the-time
#13
Schuyler Lee, Zhongzhou Chen, Gongyi Zhang
Sirtuins are a large enzyme family involved in installing and removing post-translational modifications involving lysine side chains. These enzymes have been of intense research interest and we now understand many details of their mechanism, although later steps of the deacetylase activity have remained a mystery. In this issue of Cell Chemical Biology, Wang et al. (2017) capture a late intermediate of SIRT2 catalysis and describe its structure.
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28306499/a-double-click-for-illuminating-plant-cell-walls
#14
Yuki Tobimatsu
In this issue of Cell Chemical Biology, Lion et al. (2017) report a multiplexed labeling method to visualize plant cell wall lignification in vivo. This approach uses two different lignin precursor analogs tagged with azide and alkyne reporters that can be independently incorporated into cell walls, then differentially derivatized in vivo via two bioorthogonal click reactions: strain-promoted and copper-assisted azide-alkyne cycloadditions.
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28306498/elevation-of-fumarate-levels-compromise-redox-control-and-viability-in-mycobacterium-tuberculosis
#15
Yong-Mo Ahn, Helena I Boshoff
In this issue of Cell Chemical Biology, Ruecker et al. (2017) show that fumarase depletion in Mycobacterium tuberculosis leads to fumarate, a TCA cycle intermediate, accumulation, causing succination of a range of thiol-containing metabolites and proteins. Fumarate is bactericidal to the pathogen, and its accumulation may enhance the bactericidal effector mechanisms of other TCA cycle intermediates that accumulate due to activation of infected macrophages.
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28286129/fret-based-sensors-unravel-activation-and-allosteric-modulation-of-the-gabab-receptor
#16
Nathalie Lecat-Guillet, Carine Monnier, Xavier Rovira, Julie Kniazeff, Laurent Lamarque, Jurriaan M Zwier, Eric Trinquet, Jean-Philippe Pin, Philippe Rondard
The main inhibitory neurotransmitter, γ-aminobutyric acid (GABA), modulates many synapses by activating the G protein-coupled receptor GABAB, which is a target for various therapeutic applications. It is an obligatory heterodimer made of GB1 and GB2 that can be regulated by positive allosteric modulators (PAMs). The molecular mechanism of activation of the GABAB receptor remains poorly understood. Here, we have developed FRET-based conformational GABAB sensors compatible with high-throughput screening. We identified conformational changes occurring within the extracellular and transmembrane domains upon receptor activation, which are smaller than those observed in the related metabotropic glutamate receptors...
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28286128/deacylation-mechanism-by-sirt2-revealed-in-the-1-sh-2-o-myristoyl-intermediate-structure
#17
Yi Wang, Yi Man Eva Fung, Weizhe Zhang, Bin He, Matthew Wai Heng Chung, Jing Jin, Jing Hu, Hening Lin, Quan Hao
Sirtuins are NAD-dependent deacylases. Previous studies have established two important enzymatic intermediates in sirtuin-catalyzed deacylation, an alkylamidate intermediate I, which is then converted to a bicyclic intermediate II. However, how intermediate II is converted to products is unknown. Based on potent SIRT2-specific inhibitors we developed, here we report crystal structures of SIRT2 in complexes with a thiomyristoyl lysine peptide-based inhibitor and carba-NAD or NAD. Interestingly, by soaking crystals with NAD, we capture a distinct covalent catalytic intermediate (III) that is different from the previously established intermediates I and II...
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28286127/hedgehog-signaling-from-basic-biology-to-cancer-therapy
#18
REVIEW
Fujia Wu, Yu Zhang, Bo Sun, Andrew P McMahon, Yu Wang
The Hedgehog (HH) signaling pathway was discovered originally as a key pathway in embryonic patterning and development. Since its discovery, it has become increasingly clear that the HH pathway also plays important roles in a multitude of cancers. Therefore, HH signaling has emerged as a therapeutic target of interest for cancer therapy. In this review, we provide a brief overview of HH signaling and the key molecular players involved and offer an up-to-date summary of our current knowledge of endogenous and exogenous small molecules that modulate HH signaling...
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28262560/bliss-a-bioorthogonal-dual-labeling-strategy-to-unravel-lignification-dynamics-in-plants
#19
Cedric Lion, Clémence Simon, Brigitte Huss, Anne-Sophie Blervacq, Louis Tirot, Djadidi Toybou, Corentin Spriet, Christian Slomianny, Yann Guerardel, Simon Hawkins, Christophe Biot
A better in vivo understanding of lignin formation within plant cell walls will contribute to improving the valorization of plant-derived biomass. Although bioorthogonal chemistry provides a promising platform to study the lignification process, methodologies that simultaneously detect multiple chemical reporters in living organisms are still scarce. Here, we have developed an original bioorthogonal labeling imaging sequential strategy (BLISS) to visualize and analyze the incorporation of both p-hydroxyphenyl (H) and guaiacyl (G) units into lignin in vivo with a combination of strain-promoted and copper-catalyzed azide-alkyne cycloadditions...
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28262559/directed-evolution-of-a-bright-near-infrared-fluorescent-rhodopsin-using-a-synthetic-chromophore
#20
Lukas Herwig, Austin J Rice, Claire N Bedbrook, Ruijie K Zhang, Antti Lignell, Jackson K B Cahn, Hans Renata, Sheel C Dodani, Inha Cho, Long Cai, Viviana Gradinaru, Frances H Arnold
By engineering a microbial rhodopsin, Archaerhodopsin-3 (Arch), to bind a synthetic chromophore, merocyanine retinal, in place of the natural chromophore all-trans-retinal (ATR), we generated a protein with exceptionally bright and unprecedentedly red-shifted near-infrared (NIR) fluorescence. We show that chromophore substitution generates a fluorescent Arch complex with a 200-nm bathochromic excitation shift relative to ATR-bound wild-type Arch and an emission maximum at 772 nm. Directed evolution of this complex produced variants with pH-sensitive NIR fluorescence and molecular brightness 8...
March 16, 2017: Cell Chemical Biology
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