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Biochemical Journal

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https://www.readbyqxmd.com/read/28536157/identification-of-a-conformational-heparin-recognition-motif-on-the-peptide-hormone-secretin-key-role-for-cell-surface-binding
#1
Noe Quittot, Phuong Trang Nguyen, Armelle Tchoumi Nerée, Marc P Lussier, Steve Bourgault
Secretin is a peptide hormone that exerts pleiotropic physiological functions by specifically binding to its cognate membrane-bound receptor. The membrane catalysis model of peptide-receptor interactions states that soluble peptidic ligands initially interact with the plasma membrane. This interaction increases the local concentration and structures the peptide, enhancing the rate of receptor binding. However, this model does not consider the dense network of glycosaminoglycans (GAGs) at the surface of eukaryotic cells...
May 23, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28533266/non-linearity-of-the-collagen-triple-helix-in-solution-and-implications-for-collagen-function
#2
Kenneth T Walker, Ruodan Nan, David W Wright, Jayesh Gor, Anthony C Bishop, George I Makhatadze, Barbara Brodsky, Stephen J Perkins
Collagen adopts a characteristic supercoiled triple helical conformation which requires a repeating (Xaa-Yaa-Gly)n sequence. Despite the abundance of collagen, a combined experimental and atomistic modelling approach has not so far quantitated the degree of flexibility seen experimentally in the solution structures of collagen triple helices. To address this question, we report an experimental study on the flexibility of varying lengths of collagen triple helical peptides, composed of six, eight, ten and twelve repeats of the most stable Pro-Hyp-Gly (POG) units...
May 22, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28526744/combining-properties-of-different-classes-of-pi3k%C3%AE-inhibitors-to-understand-molecular-features-that-confer-selectivity
#3
Grace Q Gong, Jackie D Kendall, James Mj Dickson, Gordon W Rewcastle, Christina M Buchanan, William A Denny, Peter R Shepherd, Jack U Flanagan
Phosphoinositide 3-kinases (PI3K) are major regulators of many cellular functions, and hyperactivation of PI3K cell signalling pathways is a major target for anticancer drug discovery. PI3Kα is the isoform most implicated in cancer, and our aim is to selectively inhibit this isoform, which may be more beneficial than concurrent inhibition of all Class I PI3Ks. We have used structure-guided design to merge high selectivity and high affinity characteristics found in existing compounds. Molecular docking including the prediction of water-mediated interactions, was used to model interactions between the ligands and the PI3Kα affinity pocket...
May 19, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28526743/systematic-identification-of-functional-residues-of-artemisia-annua-amorpha-4-11-diene-synthase
#4
Xin Fang, Jian-Xu Li, Jin-Quan Huang, You-Li Xiao, Peng Zhang, Xiao-Ya Chen
Terpene synthases (TPSs) are responsible for the extremely diversified and complex structure of terpenoids. Amorpha-4,11-diene synthase (ADS) has a high (90%) fidelity in generating the sesquiterpene precursor for biosynthesis of artemisinin, an antimalarial drug, however, little is known about how active site residues of ADS involved in the carbocation rearrangement and cyclization reactions. Here, we identify seven residues that are key to most of the catalytic steps in ADS. By structural modeling and amino acid sequence alignments of ADS with two functionally relevant sesquiterpene synthases from Artemisia annua, we performed site-directed mutagenesis and found that a single substitution, T296V, impaired the ring closure activity almost completely, and tetra-substitutions (L374Y/L404V/L405I/G439S) led to an enzyme generating 80% monocyclic bisabolyl-type sesquiterpenes, whereas a double mutant (T399L/T447G) showed compromised activity in regioselective deprotonation to yield 34...
May 19, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28522638/a-self-consistent-structural-perturbation-approach-for-determining-the-magnitude-and-extent-of-allosteric-coupling-in-proteins
#5
Nandakumar Rajasekaran, Athi N Naganathan
Elucidating the extent of energetic coupling between residues in single-domain proteins, a fundamental determinant of allostery, information transfer and folding cooperativity, has remained a grand challenge. While several sequence- and structure-based approaches have been proposed, a self-consistent description that is simultaneously compatible with unfolding thermodynamics is lacking. We had recently developed a simple structural perturbation protocol that captures the changes in thermodynamic stabilities induced by point mutations within the protein interior...
May 18, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28515264/functional-characterization-of-the-copper-transcription-factor-mrpa%C3%A2-from-aspergillus-fumigatus
#6
Yong-Sung Park, Tae-Hyoung Kim, Cheol-Won Yun
Although copper functions as a cofactor in many physiological processes, copper overload leads to harmful effects in living cells. Thus, copper homeostasis is tightly regulated. However, detailed copper metabolic pathways have not yet been identified in filamentous fungi. In this report, we investigated the copper transcription factor AfMac1 (Aspergillus fumigatus Mac1 homologue), and identified its regulatory mechanism in A. fumigatus AfMac1 has domains homologous to the DNA- and copper-binding domains of Mac1 from Saccharomyces cerevisiae , and AfMac1 efficiently complemented Mac1 in S...
May 17, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28515263/ligand-induced-activation-of-human-trpm2-requires-the-terminal-ribose-of-adpr-and-involves-arg-1433-and-tyr-1349
#7
Ralf Fliegert, Joanna M Watt, Anja Schöbel, Monika D Rozewitz, Christelle Moreau, Tanja Kirchberger, Mark P Thomas, Wiebke Sick, Andrea C Araujo, Angelika Harneit, Barry Vl Potter, Andreas H Guse
TRPM2 is a Ca(2+)-permeable non-selective cation channel activated by binding of adenosine 5'-diphosphoribose (ADPR) to its cytoplasmic NUDT9H domain. Activation of TRPM2 by ADPR downstream of oxidative stress has been implicated in the pathogenesis of a number of human diseases rendering TRPM2 an attractive novel target for pharmacological intervention. However, the structural basis underlying this activation is largely unknown. Since ADP alone did not activate or antagonize the channel, we used a chemical biology approach employing synthetic analogues to focus on the role of the ADPR terminal ribose...
May 17, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28512205/phorbol-12-myristate-13-acetate-mediated-stabilization-of-leukemia-inhibitory-factor-lif-mrna-involvement-of-nucleolin-and-pcbp1
#8
Alina Chakraborty, Srimoyee Mukherjee, Sucharita Saha, Soumasree De, Sumita Sengupta Bandyopadhyay
LIF is a potent pleiotropic cytokine involved in diverse biological activities, thereby requiring precise spatial and temporal control of its expression. The present study reveals that enhanced expression of Leukemia Inhibitory Factor in response to PMA (phorbol-12-myristate-13-acetate) in human histiocytic lymphoma cell-line U937 largely happens through stabilization of its mRNA. Functional characterization of the long 3'-untranslated region (3'-UTR) of human lif -mRNA revealed several conserved sequences with conventional cis -acting elements...
May 16, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28512204/the-human-rna-binding-protein-rbfa-promotes-the-maturation-of-the-mitochondrial-ribosome
#9
Agata Rozanska, Ricarda Richter-Dennerlein, Joanna Rorbach, Fei Gao, Richard J Lewis, Zofia M Chrzanowska-Lightowlers, Robert N Lightowlers
Accurate assembly and maturation of human mitochondrial ribosomes is essential for synthesis of the 13 polypeptides encoded by the mitochondrial genome. This process requires the correct integration of 80 proteins, 1 mt-tRNA and 2 mt-rRNA species, the latter being post-transcriptionally modified at a number of sites. Here, we report that human RBFA is a mitochondrial RNA-binding protein that exerts crucial roles in mitoribosome biogenesis. Unlike its bacterial orthologue, RBFA associates mainly with helix 44 and 45 of the 12S rRNA in the mitoribosomal small subunit to promote dimethylation of 2 highly conserved consecutive adenines...
May 16, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28512203/the-mechanism-of-activation-of-irak1-and-irak4-by-interleukin-1-and-toll-like-receptor-agonists
#10
Stefan Vollmer, Sam Strickson, Tinghu Zhang, Nathanael Gray, Katherine Lee, Vikram Rao, Philip Cohen
We have developed the first assays that measure the protein kinase activities of Interleukin-1 Receptor Associated Kinase 1 (IRAK1) and IRAK4 reliably in human cell extracts, by employing Pellino1 as a substrate in conjunction with specific pharmacological inhibitors of IRAK1 and IRAK4. We exploited these assays to show that IRAK4 was constitutively active and that its intrinsic activity towards Pellino1 was not increased significantly by stimulation with interleukin-1 (IL-1) in IL-1R-expressing HEK293 cells, Pam3Csk4-stimulated human THP1 monocytes or primary human macrophages...
May 16, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28507161/interleukin-1-and-traf6-dependent-activation-of-tak1-in-the-absence-of-tab2-and-tab3
#11
Jiazhen Zhang, Thomas Macartney, Mark Peggie, Philip Cohen
Interleukin-1 (IL-1) signaling induces the formation of Lys63-linked ubiquitin (K63-Ub) chains, which are thought to activate the "master" protein kinase TAK1 by interacting with its TAB2 and TAB3 subunits. Here, we report that IL-1b can also activate the TAB1-TAK1 heterodimer present in TAB2/TAB3 double knock-out (DKO) IL-1 receptor-expressing cells. The IL-1b-dependent activation of the TAB1-TAK1 heterodimer in TAB2/3 DKO cells required the expression and E3 ligase activity of TRAF6 and was reduced by the siRNA knock-down of Ubc13, an E2 conjugating enzyme that directs the formation of K63-Ub chains...
May 15, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28495860/p2x7-receptor-crosstalk-regulates-atp-induced-pannexin-1-internalization
#12
Andrew K J Boyce, Leigh A Swayne
In the nervous system, extracellular ATP levels transiently increase in physiological and pathophysiological circumstances, effecting key signalling pathways in plasticity and inflammation through purinergic receptors. Pannexin 1 (Panx1) forms ion and metabolite-permeable channels that mediate ATP release and are particularly enriched in the nervous system. Our recent study demonstrated that elevation of extracellular ATP triggers Panx1 internalization in a concentration and time-dependent manner. Notably, this effect was sensitive to inhibition of ionotropic P2X7 purinergic receptors (P2X7Rs)...
May 11, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28495859/alpha-synuclein-may-cross-bridge-v-snare-and-acidic-phospholipids-to-facilitate-snare-dependent-vesicle-docking
#13
Xiaochu Lou, Jaewook Kim, Brenden J Hawk, Yeon-Kyun Shin
Misfolded α-synuclein/A-syn is widely recognized as primal cause of neurodegenerative diseases including Parkinson's and dementia with Lewy bodies. The normal cellular function of A-syn has however been elusive. There is evidence that A-syn plays a variety of roles in the exocytotic pathway in the neuron, but the underlying molecular mechanisms are unclear. A-syn has been known to interact with negatively charged phospholipids and with vesicle SNARE protein VAMP2 as well. Using single vesicle-vesicle docking/fusion assays, we find that A-syn promotes SNARE-dependent vesicles docking significantly at 2...
May 11, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28495858/comparative-functional-analysis-of-ribonuclease-1-homologs-molecular-insights-into-evolving-vertebrate-physiology
#14
Jo E Lomax, Chelcie H Eller, Ronald T Raines
Pancreatic-type ribonucleases (ptRNases) comprise a class of highly conserved secretory endoribonucleases in vertebrates. The prototype of this enzyme family is ribonuclease 1 (RNase 1). Understanding the physiological roles of RNase 1 is becoming increasingly important, as engineered forms of the enzyme progress through clinical trials as chemotherapeutic agents for cancer. Here we present an in-depth biochemical characterization of RNase 1 homologs from a broad range of mammals (human, bat, squirrel, horse, cat, mouse, and cow) and non-mammalian species (chicken, lizard, and frog)...
May 11, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28487379/1-n-histidine-phosphorylation-of-chld-by-the-aaa-chli2-stimulates-magnesium-chelatase-activity-in-chlorophyll-synthesis
#15
Artur Sawicki, Shuaixiang Zhou, Kathrin Kwiatkowski, Meizhong Luo, Robert D Willows
Magnesium chelatase inserts magnesium into protoporphyrin during the biosynthesis of chlorophyll and bacteriochlorophyll. Enzyme activity is reconstituted by forming two separate pre-activated complexes consisting of a GUN4/ChlH/protoporphyrin IX substrate complex and a ChlI/ChlD enzyme "motor" complex . Formation of the ChlI/ChlD complex in both Chlamydomonas reinhardtii and Oryza sativa is accompanied by phosphorylation of ChlD by ChlI, but the orthologous protein complex from R. capsulatus, BchI/BchD, gives no detectable phosphorylation of BchD...
May 9, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28487378/encephalomyocarditis-virus-3c-protease-attenuates-type-i-interferon-production-through-disrupting-tank-tbk1-ikk%C3%AE%C2%B5-irf3-complex
#16
Li Huang, Tao Xiong, Huibin Yu, Quan Zhang, Kunli Zhang, Changyao Li, Liang Hu, Yuanfeng Zhang, Lijie Zhang, Qinfang Liu, Shengnan Wang, Xijun He, Zhigao Bu, Xuehui Cai, Shangjin Cui, Jiangnan Li, Changjiang Weng
TRAF family member-associated NF-κB activator (TANK) is a scaffold protein that assembles into the interferon regulator factor 3 (IRF3)-phosphorylating TBK1-IKKε complex, where it is involved in regulating phosphorylation of the IRF3 and interferon (IFN) production. However, the functions of TANK in Encephalomyocarditis virus (EMCV) infection-induced type I IFN production are not fully understood. Here, we demonstrated that, instead of stimulating type I IFN production, the EMCV-HB10 strain infection potently inhibited Sendai virus (SeV)- and polyI:C-induced IRF3 phosphorylation and type I IFN production in HEK293T cells...
May 9, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28476776/cytosine-methylation-by-dnmt2-facilitates-stability-and-survival-of-hiv-1-rna-in-the-host-cell-during-infection
#17
Rachana Roshan Dev, Rakesh Ganji, Satya Prakash Singh, S Mahalingam, Sharmistha Banerjee, Sanjeev Khosla
The enigmatic methyltransferase, DNMT2, structurally resembles a DNA methyltransferase but has been shown to be a tRNA methyltransferase targeting cytosine within a specific CpG in different tRNA molecules. We had previously shown that, during environmental stress conditions, DNMT2 is relocalized from the nucleus to the cytoplasmic stress granules and is associated with RNA processing proteins. In this study, we show that DNMT2 binds and methylates various mRNA species in a sequence-independent manner and gets relocalized to stress granules in a phosphorylation dependent manner...
May 5, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28468838/hiv-1-tat-potently-stabilizes-mdm2-and-enhances-viral-replication
#18
Rameez Raja, Larance Ronsard, Sneh Lata, Shubhendu Trivedi, Akhil C Banerjea
Murine double minute 2 (Mdm2) is known to enhance the transactivation potential of human immunodeficiency virus (HIV-1) Tat protein by ubiquitinating it. However, the regulation of Mdm2 during HIV-1 infection and its implications on viral replication have not been well studied. Here, we show that the Mdm2 protein level increases during HIV-1 infection and this effect is mediated by HIV-1 Tat protein. Tat appears to stabilise Mdm2 at the post-translational level by inducing its phosphorylation at serine-166 position through AKT...
May 3, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28455390/global-functions-of-extracellular-transmembrane-and-cytoplasmic-domains-of-organic-solute-transporter-%C3%AE-subunit
#19
Whitney V Christian, Patricia M Hinkle
Transport of bile acids across the basolateral membrane of the intestinal enterocyte is carried out by the organic solute transporter (Ost) composed of a seven-transmembrane domain (TMD) subunit (Osta) and an ancillary single TMD subunit (Ostb). Although previous investigations have demonstrated the importance of the TMD of Ostb for its activity, further studies were conducted to assess the contributions of other regions of the Ostb subunit. Transport activity was retained when Ostb was truncated to contain only the TMD with 15 additional residues on each side and co-expressed with Osta, whereas shorter fragments were inactive...
April 28, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28432261/ccm2-and-pak4-act-downstream-of-atrial-natriuretic-peptide-signaling-to-promote-cell-spreading
#20
Koichi Miura, Takashi Nojiri, Yoshiharu Akitake, Koji Ando, Shigetomo Fukuhara, Masahiro Zenitani, Toru Kimura, Jun Hino, Mikiya Miyazato, Hiroshi Hosoda, Kenji Kangawa
Atrial natriuretic peptide (ANP) is a cardiac hormone released by the atrium in response to stretching forces. Via its receptor, guanylyl cyclase-A (GC-A), ANP maintains cardiovascular homeostasis by exerting diuretic, natriuretic, and hypotensive effects mediated in part by endothelial cells. Both in vivo and in vitro , ANP enhances endothelial barrier function by reducing RhoA activity and reorganizing the actin cytoskeleton. We established mouse endothelial cells that stably express GC-A, and used them to analyze the molecular mechanisms responsible for actin reorganization...
April 21, 2017: Biochemical Journal
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