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Journal of Biological Chemistry

Carla Gottschald Chiodi, Daniel T Baptista-Hon, William N Hunter, Tim G Hales
GABAA receptors (GABAARs) are pentameric ligand-gated ion channels that mediate synaptic inhibition throughout the central nervous system. The α1β2γ2 receptor is the major subtype in the brain; GABA binds at the β2(+)α1(-) interface. The structure of the homomeric β3 GABAAR, which is not activated by GABA, has been solved. Recently, four additional heteromeric structures were reported, highlighting key residues required for agonist binding. Here, we used a protein engineering method, taking advantage of knowledge of the key binding residues, to create a β3(+)α1(-) heteromeric interface in the homomeric human β3 GABAAR that enables GABA-mediated activation...
December 13, 2018: Journal of Biological Chemistry
Jing Zhi Anson Tan, Paul A Gleeson
Amyloid precursor protein (APP) is processed along the amyloidogenic pathway by the β-secretase, BACE1, generating amyloid-β (Aβ), or along the non-amyloidogenic pathway by α-secretase, precluding Aβ production. The plasma membrane is considered the major site for α-secretase-mediated APP cleavage, but other cellular locations have not been rigorously investigated. Here, we report that APP is processed by endogenous α-secretase at the trans -Golgi network (TGN) of both transfected HeLa cells and mouse primary neurons...
December 13, 2018: Journal of Biological Chemistry
Christian Opitz, Erik Ahrné, Kenneth N Goldie, Alexander Schmidt, Stephan Grzesiek
Substitution of protium (H) for deuterium (D) strongly affects biological systems. Whereas higher eukaryotes such as plants and mammals hardly survive a deuterium content of > 30%, many microorganisms can grow on fully deuterated media, albeit at reduced rates. Very little is known about how the H/D replacement influences life at the systems level. Here, we used MS-based analysis to follow the adaptation of a large part of the Escherichia coli proteome from growth on a protonated full medium, over a protonated minimal medium, to a completely deuterated minimal medium...
December 13, 2018: Journal of Biological Chemistry
Afsana Sabrin, Brennan W Gioe, Ashish Gupta, Anne Grove
The antibiotic trimethoprim is frequently used to manage Burkholderia infections, and members of the resistance-nodulation-division (RND) family of efflux pumps have been implicated in multidrug resistance of this species complex. We show here that a member of the distinct Escherichia coli multidrug resistance B (EmrB) family is a primary exporter of trimethoprim in Burkholderia thailandensis , as evidenced by increased trimethoprim sensitivity after inactivation of emrB , the gene that encodes EmrB. We also found that the emrB gene is up-regulated following addition of gentamicin and that this up-regulation is due to repression of the gene encoding OstR, a member of the multiple antibiotic resistance regulator (MarR) family...
December 13, 2018: Journal of Biological Chemistry
Aruna Bitra, Tzanko Doukov, Giuseppe Destito, Michael Croft, Dirk M Zajonc
The interaction between the receptor 4-1BB and its ligand 4-1BBL provides co-stimulatory signals for T-cell activation and proliferation. However, differences in the mouse and human molecules might result in differential engagement of this pathway. Here, we report the crystal structure of mouse 4-1BBL and of the mouse 4-1BB/4-1BBL complex, which together provided insights into the molecular mechanism by which m4-1BBL and its cognate receptor recognize each other. Unlike all human or mouse tumor necrosis factor ligands that form non-covalent and mostly trimeric assemblies, the m4-1BBL structure formed a disulfide-linked dimeric assembly...
December 13, 2018: Journal of Biological Chemistry
Kristie Darrah, Ting Wang, Ian Cook, Mary Cacace, Alexander Deiters, Thomas S Leyh
Catecholamine neurotransmitter levels in the synapses of the brain shape human disposition - cognitive flexibility, aggression, depression, reward seeking… - and manipulating these levels is a major objective of the pharmaceutical industry. Certain neurotransmitters are extensively sulfonated and inactivated by human sulfotransferase 1A3 (SULT1A3). To our knowledge, sulfonation as therapeutic means of regulating transmitter activity has not been explored. Here we describe the discovery of a SULT1A3 allosteric site that can be used to inhibit the enzyme...
December 13, 2018: Journal of Biological Chemistry
Laura J Sharpe, Vicky Howe, Nicola A Scott, Winnie Luu, Lisa Phan, Jason M Berk, Mark Hochstrasser, Andrew J Brown
The E3 ligase membrane-associated ring-CH-type finger 6 (MARCH6) is a polytopic enzyme bound to the membranes of the endoplasmic reticulum. It controls levels of several known protein substrates, including a key enzyme in cholesterol synthesis, squalene monooxygenase. However, beyond its own autodegradation, little is known about how MARCH6 itself is regulated. Using CRISPR/Cas9 gene-editing, MARCH6 overexpression, and immunoblotting, we found here that cholesterol stabilizes MARCH6 protein endogenously and in HEK293 cells that stably express MARCH6...
December 13, 2018: Journal of Biological Chemistry
Shinya Ito, Kazuhiro Nagata
Heat shock protein 47 (Hsp47) is an endoplasmic reticulum (ER)-resident molecular chaperone essential for correct folding of procollagen in mammalian cells. In this review, we discuss the role and function of Hsp47 in vertebrate cells and its role in connective tissue disorders. Hsp47 binds to collagenous (Gly-Xaa-Arg) repeats within triple-helical procollagen in the ER and can prevent its local unfolding or aggregate formation, resulting in accelerating triple-helix formation of procollagen. Hsp47 pH-dependently dissociates from procollagen in the cis -Golgi or ER-Golgi intermediate compartment and is then transported back to the ER...
December 12, 2018: Journal of Biological Chemistry
Xiunan Yi, Eric J Verbeke, Yiran Chang, Daniel J Dickinson, David W Taylor
Cryo-electron microscopy (cryo-EM) has become an indispensable tool for structural studies of biological macromolecules. Two additional predominant methods are available for studying the architectures of multi-protein complexes: (1) single-particle analysis of purified samples and (2) tomography of whole cells or cell sections. The former can produce high-resolution structures but is limited to highly purified samples, whereas the latter can capture proteins in their native state but has a low signal-to-noise ratio and yields lower-resolution structures...
December 12, 2018: Journal of Biological Chemistry
Naoko Adachi, Douglas Thomas Hess, Mika Kaku, Chie Ueda, Chisato Numa, Naoaki Saito
With few reported exceptions, G protein-coupled receptors (GPCRs) are modified by Cys palmitoylation ( S -palmitoylation). In multiple GPCRs, S -pamitoylation targets a canonical site within the C-terminal cytoplasmic tail adjacent to the C-terminus of the seventh trans-membrane domain, but modification of additional sites is exemplified by the β-adrenergic receptors (βARs). The β1 AR is S -palmitoylated at a second, more distal site within the C-terminal tail and the β2 AR is modified at a second site within the third intracellular loop, neither of which is conserved in other βAR isoforms...
December 12, 2018: Journal of Biological Chemistry
Sita Nirupama Nishtala, Avish Arora, Jorge Reyes, Myles H Akabas
Infection with Plasmodium species parasites causes malaria. Plasmodium parasites are purine auxotrophic. They import purines via an equilibrative nucleoside transporter (ENT). In P. falciparum , the most virulent species, the equilibrative nucleoside transporter 1 (PfENT1) represents the primary purine uptake pathway. This transporter is a potential target for the development of antimalarial drugs. In the absence of a high-resolution structure for either PfENT1 or a homologous ENT, we used the substituted cysteine accessibility method (SCAM) to investigate the membrane-spanning domain structure of PfENT1 to identify potential inhibitor-binding sites...
December 12, 2018: Journal of Biological Chemistry
Wayne S Kontur, Charles N Olmsted, Larissa M Yusko, Alyssa V Niles, Kevin A Walters, Emily T Beebe, Kirk A Vander Meulen, Steven D Karlen, Daniel L Gall, Daniel R Noguera, Timothy J Donohue
Lignin is a heterogeneous polymer of aromatic subunits that is a major component of lignocellulosic plant biomass. Understanding how microorganisms deconstruct lignin is important for understanding the global carbon cycle, and could aid in developing systems for processing plant biomass into valuable commodities. Sphingomonad bacteria use stereospecific glutathione S-transferases (GSTs) called β-etherases to cleave the β-aryl ether (β-O-4) bond, the most common bond between aromatic subunits in lignin. Previously characterized bacterial β-etherases are homodimers that fall into two distinct GST subclasses: LigE homologues, which cleave the β( R ) stereoisomer of the bond, and LigF homologues, which cleave the β( S ) stereoisomer...
December 12, 2018: Journal of Biological Chemistry
Uladzimir Barayeu, Mike Lange, Lucía Méndez, Jürgen Arnhold, Oleg I Shadyro, Maria Fedorova, Jörg Flemmig
Cytochrome c (cyt c) is a small hemoprotein involved in electron shuttling in the mitochondrial respiratory chain and is now also recognized as an important mediator of apoptotic cell death. Its role in inducing programmed cell death is closely associated with the formation of a complex with the mitochondrion-specific phospholipid cardiolipin (CL), leading to a gain of peroxidase activity. Yet the molecular mechanisms behind this gain and eventual cyt c auto-inactivation via its release from mitochondria membranes remains largely unknown...
December 12, 2018: Journal of Biological Chemistry
Corinna Schiano di Cola, Nanna Røjel, Kenneth Jensen, Jeppe Kari, Trine Holst Sørensen, Kim Borch, Peter Westh
Glycoside hydrolase family 7 (GH7) cellulases are some of the most efficient degraders of cellulose, making them particularly relevant for industries seeking to produce renewable fuels from lignocellulosic biomass. The secretome of the cellulolytic model fungus Trichoderma reesei contains two GH7s, termed TrCel7A and TrCel7B. Despite having high structural and sequence similarities, the two enzymes are functionally quite different. TrCel7A is an exolytic, processive cellobiohydrolase (CBH), with high activity on crystalline cellulose, whereas TrCel7B is an endoglucanase (EG) with a preference for more amorphous cellulose...
December 11, 2018: Journal of Biological Chemistry
Samuel Mon-Wei Yu, Pierre-Yves Jean-Charles, Dennis M Abraham, Suneet Kaur, Clarice Gareri, Lan Mao, Howard A Rockman, Sudha K Shenoy
Reversible ubiquitination of G protein-coupled receptors regulates their trafficking and signaling; whether deubiquitinases regulate myocardial β1-adrenergic receptors (β1ARs) is unknown. We report that ubiquitin specific protease 20 (USP20) de-ubiquitinates and attenuates lysosomal trafficking of the β1AR.  β1AR-induced phosphorylation of USP20 Ser333 by protein kinase A-α (PKAα) was required for optimal USP20-mediated regulation of β1AR lysosomal trafficking. Both phospho-mimetic (S333D) and phosphorylation-impaired (S333A) USP20 possess intrinsic deubiquitinase activity equivalent to WT activity...
December 11, 2018: Journal of Biological Chemistry
Giulia Bandini, Deborah R Leon, Carolin M Hoppe, Yue Zhang, Carolina Agop-Nersesian, Melanie J Shears, Lara K Mahal, Françoise H Routier, Catherine E Costello, John Samuelson
Toxoplasma gondii is an intracellular parasite that causes disseminated infections that can produce neurological damage in fetuses and immunocompromised individuals. Microneme protein 2 (MIC2), a member of the thrombospondin-related anonymous protein (TRAP) family, is a secreted protein important for T. gondii motility, host cell attachment, invasion, and egress. MIC2 contains six thrombospondin type I repeats (TSRs) that are modified by C -mannose and O -fucose in Plasmodium spp. and mammals. Here, using MS analysis, we found that the four TSRs in T...
December 11, 2018: Journal of Biological Chemistry
Erin L McCarthy, Ananda N Rankin, Zerick R Dill, Squire J Booker
The lipoyl cofactor plays an integral role in several essential biological processes. The last step in its de novo biosynthetic pathway, the attachment of two sulfur atoms at C6 and C8 of an n -octanoyl-lysyl chain, is catalyzed by lipoyl synthase (LipA), a member of the radical SAM superfamily. In addition to the [4Fe-4S] cluster common to all radical SAM enzymes, LipA contains a second [4Fe-4S] auxiliary cluster, which is sacrificed during catalysis to supply the requisite sulfur atoms, rendering the protein inactive for further turnovers...
December 11, 2018: Journal of Biological Chemistry
Susie Son, Laura E Bowie, Tamara Maiuri, Claudia L K Hung, Carly R Desmond, Jianrun Xia, Ray Truant
Huntington's disease (HD) is a neurodegenerative, age-onset disorder caused by a CAG DNA expansion in exon 1 of the HTT gene, resulting in a polyglutamine expansion in the huntingtin protein. Nuclear accumulation of mutant huntingtin is a hallmark of HD, resulting in elevated mutant huntingtin levels in cell nuclei. Huntingtin is normally retained at the endoplasmic reticulum via its N17 amphipathic alpha-helix domain but is released by oxidation of methionine eight during reactive oxygen species (ROS) stress...
December 11, 2018: Journal of Biological Chemistry
Colin T Stomberski, Hua-Lin Zhou, Liwen Wang, Focco van den Akker, Jonathan S Stamler
Protein S-nitrosylation mediates a large part of nitric oxide's influence on cellular function by providing a fundamental mechanism to control protein function across different species and cell types. At a steady state, cellular S-nitrosylation reflects dynamic equilibria between S-nitrosothiols (SNOs) in proteins and small molecules (low-molecular-weight SNOs) whose levels are regulated by dedicated S-nitrosylases and denitrosylases. S-nitroso-coenzyme A (SNO-CoA) and its cognate denitrosylases, SNO-CoA reductases (SCoRs), are newly identified determinants of protein S-nitrosylation in both yeast and mammals...
December 11, 2018: Journal of Biological Chemistry
Lei Chen, Qinhui Liu, Qin Tang, Jiangying Kuang, Hong Li, Shiyun Pu, Tong Wu, Xuping Yang, Rui Li, Jinhang Zhang, Zijing Zhang, Ya Huang, Yanping Li, Min Zou, Wei Jiang, Tao Li, Meng Gong, Lu Zhang, Hua Wang, Aijuan Qu, Wen Xie, Jinhan He
Sirt6 is nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase with a critical role of hepatic lipid metabolism. Ketogenesis is controlled by a signaling network of hepatic lipid metabolism. However, how Sirt6 functions in ketogenesis remains unclear. Here, we demonstrated that Sirt6 functions as a mediator of ketogenesis in response to a fasting and ketogenic diet (KD). The KD-fed hepatocyte-specific Sirt6 deficiency (HKO) mice exhibited impaired ketogenesis, which was due to enhanced fat-specific induction of protein 27 (Fsp27), a protein known to regulate lipid metabolism...
December 10, 2018: Journal of Biological Chemistry
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