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    Mechanism of activation of SGK3 by growth factors-via the Class 1 and Class 3 PI3Ks.
    Biochem J 2017 Nov 17. Epub 2017 Nov 17.
    MRC Protein Phosphorylation and Ubiquitylation Unit, Department of Biochemistry, University of Dundee, MSI/WTB Complex, Dow Street, DUNDEE, DD1 5EH, United Kingdom.
    Derailment of the PI3K-AGC protein kinase signalling network contributes to many human diseases including cancer. Recent work has revealed that the poorly studied AGC kinase family member, SGK3 promotes resistance to cancer therapies that target the Class 1 PI3K pathway, by substituting for loss of Akt kinase activity. SGK3 is recruited and activated at endosomes, by virtue of its PX domain binding to PtdIns(3)P. Read More

    Microvesicles derived from human Wharton's Jellymesenchymal stem cells ameliorate ischemia-reperfusion-induced renal fibrosis by releasing from G2/M cell cycle arrest.
    Biochem J 2017 Nov 17. Epub 2017 Nov 17.
    Department of Urology, Henan Provincial People's Hospital, No. 7 Weiwu Road, Zhengzhou, China
    Studies have demonstrated that microvesicles (MVs) derived from human Wharton's Jelly mesenchymal stromal cells (hWJMSCs) could ameliorate renal ischemia/reperfusion injury (IRI), however, the underlying mechanisms were not clear yet. Here, MVs were isolated and injected intravenously into rats immediately after ischemia of the left kidney, and Erk1/2 activator HGF or inhibitor U0126 was administrated, respectively. Tubular cell proliferation and apoptosis were identified by Ki67 or TUNEL immunostaining. Read More

    Biochemical characterization of INTS3 and C9ORF80, two subunits of hNABP1/2 heterotrimeric complex in nucleic acid binding.
    Biochem J 2017 Nov 17. Epub 2017 Nov 17.
    Biochemistry, University of Saskatchewan, Rm 4D01.1, HSB, 107 Wiggins Road, Saskatoon, N/A, S7N 5E5, Canada
    Human Nucleic Acid Binding Protein 1 and 2 (hNABP1 and hNABP2, also known as hSSB2 and hSSB1) form two separate and independent complexes with two identical proteins, integrator complex subunit 3 (INTS3) and C9ORF80. We and other groups have demonstrated that hNABP1 and 2 are single stranded (ss) DNA and RNA binding proteins, and function in DNA repair; however, the function of INTS3 and C9OFR80 remains elusive. In this study, we purified recombinant proteins INTS3 and C9ORF80 to near homogeneity. Read More

    Holistic bioengineering: rewiring central metabolism for enhanced bioproduction.
    Biochem J 2017 Nov 16;474(23):3935-3950. Epub 2017 Nov 16.
    Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, Potsdam-Golm 14476, Germany
    What does it take to convert a living organism into a truly productive biofactory? Apart from optimizing biosynthesis pathways as standalone units, a successful bioengineering approach must bend the endogenous metabolic network of the host, and especially its central metabolism, to support the bioproduction process. In practice, this usually involves three complementary strategies which include tuning-down or abolishing competing metabolic pathways, increasing the availability of precursors of the desired biosynthesis pathway, and ensuring high availability of energetic resources such as ATP and NADPH. In this review, we explore these strategies, focusing on key metabolic pathways and processes, such as glycolysis, anaplerosis, the TCA (tricarboxylic acid) cycle, and NADPH production. Read More

    Chloroplast division protein ARC3 acts on FtsZ2 by preventing filament bundling and enhancing GTPase activity.
    Biochem J 2017 Nov 14. Epub 2017 Nov 14.
    Biomedical Sciences, University of Texas Rio Grande Valley, 2102 Treasure Hills Blvd., Harlingen, Texas, 78550, United States.
    Chloroplasts evolved from cyanobacterial endosymbiotic ancestors and their division is a complex process initiated by assembly of cytoskeletal FtsZ proteins into a ring structure at the division site (Z-ring). The cyanobacterial Z-ring positioning system (MinCDE proteins) is also conserved in chloroplasts except that MinC was lost and replaced by the eukaryotic ARC3. Both MinC and ARC3 act as negative regulators of FtsZ assembly, but ARC3 bears little sequence similarity with MinC. Read More

    Spectroscopic and calorimetric characterization of spermine oxidase and its association forms.
    Biochem J 2017 Nov 14. Epub 2017 Nov 14.
    University of Rome, Rome, Italy
    Spermine oxidase (SMOX) is a flavin-containing enzyme that oxidizes spermine to produce spermidine, 3-aminopropanaldehyde and hydrogen peroxide. SMOX has been shown to play key roles in inflammation and carcinogenesis; indeed it is differentially expressed in several human cancer types. Our previous investigation has revealed that SMOX purified after heterologous expression in Escherichia coli actually consists of monomers, covalent homodimers, and other higher-order forms. Read More

    SUMO chain formation relies on the amino-terminal region of SUMO conjugating enzyme and has dedicated substrates in plants.
    Biochem J 2017 Nov 13. Epub 2017 Nov 13.
    Department of Biochemistry and Cell Biology, University of Vienna, Dr. Bohr Gasse 9, Vienna, A-1030, Austria
    The SUMO conjugation apparatus usually attaches single SUMO moieties to its substrates, but SUMO chains have also been identified. In order to better define biochemical requirements and characteristics of SUMO chain formation, mutations in surface-exposed Lys residues of Arabidopsis SUMO conjugating enzyme (SCE) were tested for in vitro activity. Lys to Arg changes in the amino-terminal region of SCE allowed SUMO acceptance from SUMO activating enzyme and supported substrate mono-sumoylation, but these mutations had significant effects on SUMO chain assembly. Read More

    Development of phospho-specific Rab protein antibodies to monitor in vivo activity of the LRRK2 Parkinson's disease kinase.
    Biochem J 2017 Nov 10. Epub 2017 Nov 10.
    MRC Protein Phosphorylation and Ubiquitylation Unit, Department of Biochemistry, University of Dundee, MSI/WTB Complex, Dow Street, DUNDEE, DD1 5EH, United Kingdom
    Mutations that activate the LRRK2 protein kinase, predispose to Parkinson's disease, suggesting that LRRK2 inhibitors might have therapeutic benefit. Recent work has revealed that LRRK2 phosphorylates a subgroup of 14 Rab proteins, including Rab10, at a specific residue located at the centre of its effector binding Switch-II motif. In this study, we analyse the selectivity and sensitivity of polyclonal and monoclonal phospho-specific antibodies raised against 9 different LRRK2 phosphorylated Rab proteins (Rab3A/3B/3C/3D, Rab5A/5B/5C, Rab8A/8B, Rab10, Rab12, Rab29[T71], Rab29[S72], Rab35 and Rab43). Read More

    Interrogating Parkinson's disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils.
    Biochem J 2017 Nov 10. Epub 2017 Nov 10.
    Department of Neurology, School of Medicine Dundee, Ninewells Hospital, Dundee, United Kingdom.
    There is compelling evidence for the role of LRRK2 and in particular its kinase function in Parkinson's disease. Orally bioavailable, brain penetrant and potent LRRK2 kinase inhibitors are in the later stages of clinical development. Here we describe a facile and robust assay to quantify LRRK2 kinase pathway activity by measuring LRRK2 mediated phosphorylation of Rab10 in human peripheral blood neutrophils. Read More

    Steroidogenic abnormalities in translocator protein knockout mice and significance in the aging male.
    Biochem J 2017 Nov 10. Epub 2017 Nov 10.
    QST, tbc, Japan.
    The translocator protein (TSPO) has been proposed to act as a key component in a complex important for mitochondrial cholesterol importation, which is the rate-limiting step in steroid hormone synthesis. However, TSPO function in steroidogenesis has recently been challenged by the development of TSPO knockout (TSPO-KO) mice, as they exhibit normal baseline gonadal testosterone and adrenal corticosteroid production. Here we demonstrate that despite normal androgen levels in young male TSPO-KO mice, TSPO deficiency alters steroidogenic flux and results in reduced total steroidogenic output. Read More

    First biochemical and crystallographic characterization of a fast-performing ferritin from a marine invertebrate.
    Biochem J 2017 Nov 10. Epub 2017 Nov 10.
    UC San Diego / Scripps Inst. of Oceanography, San Diego, California, United States
    Ferritin, a multimeric cage-like enzyme, is integral to iron metabolism across all phyla through the sequestration and storage of iron through efficient ferroxidase activity. While ferritin sequences from around 900 species have been identified, crystal structures from only 50 species have been reported, the majority from bacterial origin. We recently isolated a secreted ferritin from the marine invertebrate Chaetopterus sp. Read More

    Carbidopa: a selective Ah receptor modulator (SAhRM).
    Biochem J 2017 Nov 6;474(22):3763-3765. Epub 2017 Nov 6.
    Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, U.S.A.
    The aryl hydrocarbon receptor (AhR) was discovered as the intracellular receptor that bound with high affinity to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and the AhR is required for mediating the toxicity induced by TCDD. Subsequent studies show that the AhR binds structurally diverse chemicals including plant-derived compounds that promote health and several AhR-active pharmaceuticals that exhibit anticancer activity. In this issue, there is a report that carbidopa, a drug used for treating Parkinson's disease, is also an AhR ligand, and this compound inhibits pancreatic cancer cell and tumor growth. Read More

    Interplay between σ region 3.2 and secondary channel factors during promoter escape by bacterial RNA polymerase.
    Biochem J 2017 Nov 3. Epub 2017 Nov 3.
    Institute of Molecular Genetics, Russian Academy of Sciences, Kurchatov square 2, Moscow, 123182, Russia
    In bacterial RNA polymerase (RNAP), conserved region 3.2 of the σ subunit was proposed to contribute to promoter escape by interacting with the 5'-end of nascent RNA, thus facilitating σ dissociation. RNAP activity during transcription initiation can also be modulated by protein factors that bind within the secondary channel and reach the enzyme active site. Read More

    Dual Phosphorylation in Response Regulator Protein PrrA is Crucial for Intracellular Survival of Mycobacteria Consequent upon Transcriptional Activation.
    Biochem J 2017 Nov 3. Epub 2017 Nov 3.
    Microbiology, CSIR-Central Drug Research Institute, Jankipuram, Sitapur Road, Lucknow, 226031, India
    The remarkable ability of M. tuberculosis ( Mtb ) to survive inside the human macrophages is attributed to the presence of a complex sensory and regulatory network. PrrA is a DNA-binding regulatory protein, belongs to an essential two-component system (TCS), PrrA/B; which is required for early phase intracellular replication of Mtb. Read More

    GPR4 knockout improves renal ischemia-reperfusion injury and inhibits apoptosis via suppressing the expression of CHOP.
    Biochem J 2017 Oct 31. Epub 2017 Oct 31.
    The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
    The aim of this study was to investigate the effects and molecular mechanisms of GPR4 in cell apoptosis and renal ischemia-reperfusion (IR) injury in vivo and in vitroGPR4(-/-) mice and wild-type (WT) mice underwent renal IR or sham procedures. For hypoxia/reoxygenation (HR), human umbilical vein endothelial cells (HUVECs) were subjected to 4 h of hypoxia, followed by 6 h of reoxygenation. Renal histological changes were observed by periodic acid-schiff (PAS) staining and myeloperoxidase (MPO) activity. Read More

    Mitochondrial DNA Density Homeostasis Accounts for a Threshold Effect in a Cybrid Model of a Human Mitochondrial Disease.
    Biochem J 2017 Nov 10. Epub 2017 Nov 10.
    Department of Mathematics, Imperial College London, London, United Kingdom
    Mitochondrial dysfunction is involved in a wide array of devastating diseases but the heterogeneity and complexity of these diseases' symptoms challenges theoretical understanding of their causation. With the explosion of -omics data, we have the unprecedented opportunity to gain deep understanding of the biochemical mechanisms of mitochondrial dysfunction. This goal raises the need to make these complex datasets interpretable. Read More

    TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis.
    Biochem J 2017 Oct 26. Epub 2017 Oct 26.
    University of Southern California, Los Angeles, California, United States
    The 18 kDa translocator protein (TSPO) is a ubiquitous conserved outer mitochondrial membrane protein implicated in numerous cell and tissue functions, including steroid hormone biosynthesis, respiration, cell proliferation and apoptosis.  TSPO binds with high affinity to cholesterol and numerous compounds, is expressed at high levels in steroid-synthesizing tissues, and mediates cholesterol import into mitochondria, which is the rate-limiting step in steroid formation.  In humans, the rs6971 polymorphism on the TSPO gene leads to an amino acid substitution in the fifth transmembrane loop of the protein, which is where the cholesterol-binding domain of TSPO is located, and this polymorphism has been associated with anxiety-related disorders. Read More

    Engineering Oxidative Stability in Human Hemoglobin based on the Hb Providence (βK82D) mutation and Genetic Crosslinking.
    Biochem J 2017 Nov 10. Epub 2017 Nov 10.
    CBER, United States Food and Drug Administration, Silver Spring, Maryland, 20993, United States
    Previous work suggested that hemoglobin (Hb) tetramer formation slows autoxidation and hemin loss and that the naturally occurring mutant, Hb Providence (βK82D) is much more resistant to degradation by H2O2 We have examined systematically the effects of genetic crosslinking of Hb tetramers with and without the Hb Providence mutation on autoxidation, hemin loss, and reactions with H2O2, using native HbA and various wild-type recombinant Hbs as controls. Genetically crosslinked Hb Presbyterian (βN108K) was also examined as an example of a low oxygen affinity tetramer. Our conclusions are: (a) at low concentrations, all the crosslinked tetramers show smaller rates of autoxidation and hemin loss than HbA, which can dissociate into much less stable dimers and (b) the Hb Providence βK82D mutation confers more resistance to degradation by H2O2, by markedly inhibiting oxidation of the β93 cysteine side chain, particularly in crosslinked tetramers and even in the presence of the destabilizing Hb Presbyterian mutation. Read More

    The role and mechanism of action of sperm PLC-zeta in mammalian fertilisation.
    Biochem J 2017 Oct 23;474(21):3659-3673. Epub 2017 Oct 23.
    College of Medicine, Member of QU Health, Qatar University, PO Box 2713, Doha, Qatar.
    At mammalian fertilisation, the fundamental stimulus that triggers oocyte (egg) activation and initiation of early embryonic development is an acute rise of the intracellular-free calcium (Ca(2+)) concentration inside the egg cytoplasm. This essential Ca(2+) increase comprises a characteristic series of repetitive Ca(2+) oscillations, starting soon after sperm-egg fusion. Over the last 15 years, accumulating scientific and clinical evidence supports the notion that the physiological stimulus that precedes the cytosolic Ca(2+) oscillations is a novel, testis-specific phospholipase C (PLC) isoform, known as PLC-zeta (PLCζ). Read More

    Therapeutics targeting Bcl-2 in hematological malignancies.
    Biochem J 2017 Oct 23;474(21):3643-3657. Epub 2017 Oct 23.
    Roche, Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel 4070, Switzerland.
    Members of the B-cell lymphoma 2 (BCL-2) gene family are attractive targets for cancer therapy as they play a key role in promoting cell survival, a long-since established hallmark of cancer. Clinical utility for selective inhibition of specific anti-apoptotic Bcl-2 family proteins has recently been realized with the Food and Drug Administration (FDA) approval of venetoclax (formerly ABT-199/GDC-0199) in relapsed chronic lymphocytic leukemia (CLL) with 17p deletion. Despite the impressive monotherapy activity in CLL, such responses have rarely been observed in other B-cell malignancies, and preclinical data suggest that combination therapies will be needed in other indications. Read More

    Synthesis and degradation of cAMP in Giardia lamblia : possible role and characterization of a nucleotidyl cyclase with a single cyclase-homology-domain.
    Biochem J 2017 Oct 20. Epub 2017 Oct 20.
    Área de Biología Molecular, Departamento de Bioquímica y Ciencias Biológicas, Instituto Multidisciplinario de Investigaciones Biológicas de San Luis (IMIBIO-SL-CONICET)/UNSL, San Luis, N/A, Argentina
    Despite its importance in the regulation of growth and differentiation processes of a variety of organisms, the mechanism of synthesis and degradation of cAMP has not yet been described in Giardia lamblia In this work, we measured significant quantities of cAMP in trophozoites of G. lamblia incubated in vitro and later detected how it increases during the first hours of encystation, and how it then returns to basal levels at 24 h. Through an analysis of the genome of G. Read More

    Regulation of insulin-like growth factor receptors by ubiquilin1.
    Biochem J 2017 Oct 20. Epub 2017 Oct 20.
    Medicine/James Graham Brown Cancer Center, university of Louisville, Louisville, Kentucky, 40202, United States
    Insulin-like growth factor-1 receptor (IGF1R) is a receptor tyrosine kinase that mediates growth, proliferation and survival. Dysregulation of IGF pathway contributes to initiation, progression and metastasis of cancer and is also involved in diseases of glucose metabolism, such as Diabetes. We have identified Ubiquilin1 (UBQLN1) as a novel interaction partner of IGF1R, IGF2R and Insulin Receptor. Read More

    Nuclear transport of the Neurospora crassa NIT-2 transcription factor is mediated by Importin-α.
    Biochem J 2017 Oct 20. Epub 2017 Oct 20.
    Dep. Physics and Biophysics, São Paulo State University (UNESP), Rua Professor Doutor Antonio Celso Wagner Zanin, s/n, CEP 18618-689, Botucatu, 18618-689, Brazil
    The Neurospora crassa NIT-2 transcription factor belongs to the GATA transcription factor family and plays a fundamental role in the regulation of nitrogen metabolism by N. crassa Because NIT-2 acts by accessing DNA inside the nucleus, understanding the nuclear import process of NIT-2 is necessary to characterize its function. Thus, in this study, NIT-2 nuclear transport was investigated using a combination of biochemical, cellular and biophysical methods. Read More

    Recombinant human islet amyloid polypeptide forms shorter fibrils and mediates β-cell apoptosis via generation of oxidative stress.
    Biochem J 2017 Nov 16;474(23):3915-3934. Epub 2017 Nov 16.
    Department of Biosciences and Bioengineering, Indian Institute of Technology, Mumbai 400076, India
    Protein misfolding and aggregation play an important role in many human diseases including Alzheimer's, Parkinson's and type 2 diabetes mellitus (T2DM). The human islet amyloid polypeptide (hIAPP) forms amyloid plaques in the pancreas of T2DM subjects (>95%) that are involved in deteriorating islet function and in mediating β-cell apoptosis. However, the detailed mechanism of action, structure and nature of toxic hIAPP species responsible for this effect remains elusive to date mainly due to the high cost associated with the chemical synthesis of pure peptide required for these studies. Read More

    Rac1-stimulated macropinocytosis enhances Gβγ activation of PI3Kβ.
    Biochem J 2017 Nov 16;474(23):3903-3914. Epub 2017 Nov 16.
    Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, U.S.A.
    Phosphoinositide 3-kinases (PI 3-kinases) are regulated by a diverse range of upstream activators, including receptor tyrosine kinases (RTKs), G-protein-coupled receptors (GPCRs), and small GTPases from the Ras, Rho and Rab families. For the Class IA PI 3-kinase PI3Kβ, two mechanisms for GPCR-mediated regulation have been described: direct binding of Gβγ subunits to the C2-helical domain linker of p110β, and Dock180/Elmo1-mediated activation of Rac1, which binds to the Ras-Binding Domain of p110β. We now show that the integration of these dual pathways is unexpectedly complex. Read More

    Nutlin-3 plus Tanshinone IIA Exhibits Synergetic Anti-leukemia Effect with Imatinib by Reactivating p53 and Inhibiting AKT/mTOR Pathway in Ph+ ALL.
    Biochem J 2017 Oct 18. Epub 2017 Oct 18.
    West China Hospital of Sichuan University, Chengdu, N/A, China.
    Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is triggered by BCR/ABL kinase. Recent efforts focused on the development of more potent tyrosine kinase inhibitors (TKI) that also inhibit mutant tyrosine kinases such as nilotinib and dasatinib. Although major advances in the treatment of this aggressive disease with potent inhibitors of the BCR/ABL kinases, patients in remission frequently relapse due to drug resistance possibly mediated, at least in part, by compensatory activation of growth-signaling pathways and protective feedback signaling of leukemia cells in response to TKI-treatment. Read More

    GPI-anchored proteins are confined in subdiffraction clusters at the apical surface of polarized epithelial cells.
    Biochem J 2017 Oct 18. Epub 2017 Oct 18.
    Unite Trafic Membranaire et Pathogenèse, Institut Pasteur, 25, rue de Dr Roux, PARIS, 75724 CEDEX 15, France
    Spatio-temporal compartmentalization of membrane proteins is critical for the regulation of diverse vital functions in eukaryotic cells. It was previously shown that, at the apical surface of polarized MDCK cells, glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) are organized in small cholesterol-independent clusters of single GPI-AP species (homoclusters), which are required for the formation of larger cholesterol-dependent clusters formed by multiple GPI-APs species (heteroclusters). This clustered organization is crucial for the biological activities of GPI-APs, hence, understanding the spatio-temporal properties of their membrane organization is of fundamental importance. Read More

    Kinetochore-microtubule interactions in chromosome segregation: lessons from yeast and mammalian cells.
    Biochem J 2017 Oct 18;474(21):3559-3577. Epub 2017 Oct 18.
    School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, CET Campus, Thiruvananthapuram, Kerala 695016, India
    Chromosome congression and segregation require robust yet dynamic attachment of the kinetochore with the spindle microtubules. Force generated at the kinetochore-microtubule interface plays a vital role to drive the attachment, as it is required to move chromosomes and to provide signal to sense correct attachments. To understand the mechanisms underlying these processes, it is critical to describe how the force is generated and how the molecules at the kinetochore-microtubule interface are organized and assembled to withstand the force and respond to it. Read More

    OleA Glu117 is key to condensation of two fatty-acyl coenzyme A substrates in long-chain olefin biosynthesis.
    Biochem J 2017 Nov 10;474(23):3871-3886. Epub 2017 Nov 10.
    Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, U.S.A.
    In the interest of decreasing dependence on fossil fuels, microbial hydrocarbon biosynthesis pathways are being studied for renewable, tailored production of specialty chemicals and biofuels. One candidate is long-chain olefin biosynthesis, a widespread bacterial pathway that produces waxy hydrocarbons. Found in three- and four-gene clusters, oleABCD encodes the enzymes necessary to produce cis-olefins that differ by alkyl chain length, degree of unsaturation, and alkyl chain branching. Read More

    Recognition of hyperacetylated N-terminus of H2AZ by TbBDF2 from Trypanosoma brucei.
    Biochem J 2017 Nov 9;474(22):3817-3830. Epub 2017 Nov 9.
    School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
    Histone modification plays an important role in various biological processes, including gene expression regulation. Bromodomain, as one of histone readers, recognizes specifically the ε-N-lysine acetylation (KAc) of histone. Although the bromodomains and histone acetylation sites of Trypanosoma brucei (T. Read More

    Lipid-based DNA/siRNA transfection agents disrupt neuronal bioenergetics and mitophagy.
    Biochem J 2017 Nov 10;474(23):3887-3902. Epub 2017 Nov 10.
    Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, U.S.A.
    A multitude of natural and artificial compounds have been recognized to modulate autophagy, providing direct or, through associated pathways, indirect entry points to activation and inhibition. While these pharmacological tools are extremely useful in the study of autophagy, their abundance also suggests the potential presence of unidentified autophagic modulators that may interfere with experimental designs if applied unknowingly. Here, we report unanticipated effects on autophagy and bioenergetics in neuronal progenitor cells (NPCs) incubated with the widely used lipid-based transfection reagent lipofectamine (LF), which induced mitochondria depolarization followed by disruption of electron transport. Read More

    Dynamic multi-site phosphorylation by Fyn and Abl drives the interaction between CRKL and the novel scaffolding receptors DCBLD1 and DCBLD2.
    Biochem J 2017 Oct 19. Epub 2017 Oct 19.
    Department of Biology, University of Vermont, 109 Carrigan Drive, 120A MLS, Burlington, Vermont, 05405, United States
    Discoidin, CUB, and LCCL Domain-containing (DCBLD) 2 is a neuropilin-like transmembrane scaffolding receptor with known and anticipated roles in vascular remodeling and neuronal positioning. DCBLD2 is also upregulated in several cancers and can drive glioblastomas downstream of activated Epidermal Growth Factor Receptor. While a few studies have shown either a positive or negative role for DCBLD2 in regulating growth factor receptor signaling, little is known about the conserved signaling features of DCBLD family members that drive their molecular activities. Read More

    Macromolecular assemblies of complex polysaccharides with galectin-3 and their synergistic effects on function.
    Biochem J 2017 Nov 9;474(22):3849-3868. Epub 2017 Nov 9.
    Jilin Province Key Laboratory for Chemistry and Biology of Natural Drugs in Changbai Mountain, School of Life Sciences, Northeast Normal University, Changchun 130024, PR China
    Although pectin-derived polysaccharides can antagonize galectin function in various pathological disorders, the nature of their binding interactions needs to be better defined for developing them as drugs. Moreover, given their relatively large size and complexity, pectin-derived polysaccharides are also useful as model systems to assess inter-polysaccharide and protein-polysaccharide interactions. Here, we investigated interactions between galectin-3 (Gal-3) and pectin-derived polysaccharides: a rhamnogalacturonan (RG) and two homogalacturonans (HGs). Read More

    A conserved mammalian mitochondrial isoform of acetyl-CoA carboxylase ACC1 provides the malonyl-CoA essential for mitochondrial biogenesis in tandem with ACSF3.
    Biochem J 2017 Nov 6;474(22):3783-3797. Epub 2017 Nov 6.
    Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu FI-90014, Finland
    Mitochondrial fatty acid synthesis (mtFAS) is a highly conserved pathway essential for mitochondrial biogenesis. The mtFAS process is required for mitochondrial respiratory chain assembly and function, synthesis of the lipoic acid cofactor indispensable for the function of several mitochondrial enzyme complexes and essential for embryonic development in mice. Mutations in human mtFAS have been reported to lead to neurodegenerative disease. Read More

    BamA β6C strand and periplasmic turns are critical for outer membrane protein insertion and assembly.
    Biochem J 2017 Oct 3. Epub 2017 Oct 3.
    Norwich Medical School, University of East Anglia, Norwich, United Kingdom
    Outer membrane β-barrel proteins play important roles in importing nutrients, exporting wastes and conducting signals in Gram-negative bacteria, mitochondria and chloroplasts. The outer membrane proteins are inserted and assembled into the outer membrane by OMP85 family proteins. In Escherichia coli , the b-barrel assembly machinery (BAM) contains four lipoproteins BamB, BamC, BamD and BamE, and one outer membrane protein BamA, forming a "top hat"-like structure. Read More

    Depletion of MUC5B mucin in gastrointestinal cancer cells alters their tumorigenic properties: implication of the Wnt/β-catenin pathway.
    Biochem J 2017 Nov 1;474(22):3733-3746. Epub 2017 Nov 1.
    Univ. Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences and Cancer, Lille F-59000, France
    Secreted mucins are large O-glycosylated proteins that participate in the protection/defence of underlying mucosae in normal adults. Alteration of their expression is a hallmark of numerous epithelial cancers and has often been correlated to bad prognosis of the tumour. The secreted mucin MUC5B is overexpressed in certain subtypes of gastric and intestinal cancers, but the consequences of this altered expression on the cancer cell behaviour are not known. Read More

    Processing of syndecan-2 by matrix metalloproteinase-14 and effect of its cleavage on VEGF-induced tube formation of HUVECs.
    Biochem J 2017 Nov 1;474(22):3719-3732. Epub 2017 Nov 1.
    Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
    Syndecans (SDCs) are transmembrane proteoglycans that are involved in cell adhesion and cell communication. Specifically, SDC2 plays a key role in tumorigenesis, metastasis, and angiogenesis. Previously, we found that rat SDC2 is shed by matrix metalloproteinase-7 (MMP-7) in colon cancer cells. Read More

    Carbidopa is an activator of aryl hydrocarbon receptor with potential for cancer therapy.
    Biochem J 2017 Sep 28;474(20):3391-3402. Epub 2017 Sep 28.
    Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A.
    Carbidopa is used with l-DOPA (l-3,4-dihydroxyphenylalanine) to treat Parkinson's disease (PD). PD patients exhibit lower incidence of most cancers including pancreatic cancer, but with the notable exception of melanoma. The decreased cancer incidence is not due to l-DOPA; however, the relevance of Carbidopa to this phenomenon has not been investigated. Read More

    Reduction potentials of protein disulfides and catalysis of glutathionylation and deglutathionylation by glutaredoxin enzymes.
    Biochem J 2017 Nov 9;474(22):3799-3815. Epub 2017 Nov 9.
    School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia
    Glutaredoxins (Grxs) are a class of GSH (glutathione)-dependent thiol-disulfide oxidoreductase enzymes. They use the cellular redox buffer GSSG (glutathione disulfide)/GSH directly to catalyze these exchange reactions. Grxs feature dithiol active sites and can shuttle rapidly between three oxidation states, namely dithiol Grx(SH)2, mixed disulfide Grx(SH)(SSG) and oxidized disulfide Grx(SS). Read More

    Evolution of allosteric regulation in chorismate mutases from early plants.
    Biochem J 2017 Nov 1;474(22):3705-3717. Epub 2017 Nov 1.
    Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, U.S.A.
    Plants, fungi, and bacteria synthesize the aromatic amino acids: l-phenylalanine, l-tyrosine, and l-tryptophan. Chorismate mutase catalyzes the branch point reaction of phenylalanine and tyrosine biosynthesis to generate prephenate. In Arabidopsis thaliana, there are two plastid-localized chorismate mutases that are allosterically regulated (AtCM1 and AtCM3) and one cytosolic isoform (AtCM2) that is unregulated. Read More

    Onconase dimerization through 3D domain swapping: structural investigations and increase in the apoptotic effect in cancer cells.
    Biochem J 2017 Nov 6;474(22):3767-3781. Epub 2017 Nov 6.
    Dipartimento di Neuroscienze, Biomedicina e del Movimento, Sezione di Chimica Biologica, Università degli Studi di Verona, Strada Le Grazie, 8, Verona I-37134, Italy
    Onconase® (ONC), a protein extracted from the oocytes of the Rana pipiens frog, is a monomeric member of the secretory 'pancreatic-type' RNase superfamily. Interestingly, ONC is the only monomeric ribonuclease endowed with a high cytotoxic activity. In contrast with other monomeric RNases, ONC displays a high cytotoxic activity. Read More

    Sequencing of chondroitin sulfate oligosaccharides using a novel exolyase from a marine bacterium that degrades hyaluronan and chondroitin sulfate/dermatan sulfate.
    Biochem J 2017 Nov 9;474(22):3831-3848. Epub 2017 Nov 9.
    National Glycoengineering Research Center, School of Life Science and Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, 27 South Shanda Rd, Jinan 250100, PR China
    Glycosaminoglycans (GAGs) are a family of chemically heterogeneous polysaccharides that play important roles in physiological and pathological processes. Owing to the structural complexity of GAGs, their sophisticated chemical structures and biological functions have not been extensively studied. Lyases that cleave GAGs are important tools for structural analysis. Read More

    Structural complexity in the KCTD family of Cullin3-dependent E3 ubiquitin ligases.
    Biochem J 2017 Nov 1;474(22):3747-3761. Epub 2017 Nov 1.
    Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K.
    Members of the potassium channel tetramerization domain (KCTD) family are soluble non-channel proteins that commonly function as Cullin3 (Cul3)-dependent E3 ligases. Solution studies of the N-terminal BTB domain have suggested that some KCTD family members may tetramerize similarly to the homologous tetramerization domain (T1) of the voltage-gated potassium (Kv) channels. However, available structures of KCTD1, KCTD5 and KCTD9 have demonstrated instead pentameric assemblies. Read More

    Direct Visualization of Interaction between Calmodulin and Connexin45.
    Biochem J 2017 Sep 28. Epub 2017 Sep 28.
    Department of Chemistry, Georgia State University, 50 Decatur Street SE, Altanta, Georgia, 30303, United States
    Calmodulin (CaM) is an intracellular Ca(2+) transducer involved in numerous activities in a broad Ca(2+) signaling network. Previous studies have suggested that the Ca(2+)/CaM complex may participate in gap junction regulation via interaction with putative CaM-binding motifs in connexins, however, evidence of direct interactions between CaM and connexins has remained elusive to date due to challenges related to the study of membrane proteins. Here we report the first direct interaction of CaM with Cx45 of g-family in living cells under physiological conditions by monitoring bioluminescence resonance energy transfer (BRET). Read More

    Regulating protein breakdown through proteasome phosphorylation.
    Biochem J 2017 Sep 24;474(19):3355-3371. Epub 2017 Sep 24.
    Harvard Medical School, Boston, MA 02115, U.S.A.
    The ubiquitin proteasome system degrades the great majority of proteins in mammalian cells. Countless studies have described how ubiquitination promotes the selective degradation of different cell proteins. However, there is a small but the growing literature that protein half-lives can also be regulated by post-translational modifications of the 26S proteasome. Read More

    The spliceosomal proteins PPIH and PRPF4 exhibit bi-partite binding.
    Biochem J 2017 Oct 25;474(21):3689-3704. Epub 2017 Oct 25.
    Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, U.S.A.
    Pre-mRNA splicing is a dynamic, multistep process that is catalyzed by the RNA (ribonucleic acid)-protein complex called the spliceosome. The spliceosome contains a core set of RNAs and proteins that are conserved in all organisms that perform splicing. In higher organisms, peptidyl-prolyl isomerase H (PPIH) directly interacts with the core protein pre-mRNA processing factor 4 (PRPF4) and both integrate into the pre-catalytic spliceosome as part of the tri-snRNP (small nuclear RNA-protein complex) subcomplex. Read More

    Suppression of store-operated Ca(2+) entry by activation of GPER: contribution to a clamping effect on endothelial Ca(2+) signaling.
    Biochem J 2017 Oct 23;474(21):3627-3642. Epub 2017 Oct 23.
    Department of Physiology and Pharmacology, Des Moines University Osteopathic Medical Center, 3200 Grand Avenue, Des Moines, IA 50312, U.S.A.
    The G protein-coupled estrogen receptor 1 (GPER, formerly also known as GPR30) modulates many Ca(2+)-dependent activities in endothelial cells. However, the underlying mechanisms are poorly understood. We recently reported that GPER acts to prolong cytoplasmic Ca(2+) signals by interacting with and promoting inhibitory phosphorylation of the plasma membrane Ca(2+)-ATPase. Read More

    VPS18 recruits VPS41 to the human HOPS complex via a RING-RING interaction.
    Biochem J 2017 Oct 23;474(21):3615-3626. Epub 2017 Oct 23.
    Department of Pathology, University of Cambridge, Cambridge, U.K.
    Eukaryotic cells use conserved multisubunit membrane tethering complexes, including CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting), to control the fusion of endomembranes. These complexes have been extensively studied in yeast, but to date there have been far fewer studies of metazoan CORVET and HOPS. Both of these complexes comprise six subunits: a common four-subunit core and two unique subunits. Read More

    Targeting epithelial-mesenchymal plasticity in cancer: clinical and preclinical advances in therapy and monitoring.
    Biochem J 2017 Sep 20;474(19):3269-3306. Epub 2017 Sep 20.
    Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia
    The concept of epithelial-mesenchymal plasticity (EMP), which describes the dynamic flux within the spectrum of phenotypic states that invasive carcinoma cells may reside, is being increasingly recognised for its role in cancer progression and therapy resistance. The myriad of events that are able to induce EMP, as well as the more recently characterised control loops, results in dynamic transitions of cancerous epithelial cells to more mesenchymal-like phenotypes through an epithelial-mesenchymal transition (EMT), as well as the reverse transition from mesenchymal phenotypes to an epithelial one. The significance of EMP, in its ability to drive local invasion, generate cancer stem cells and facilitate metastasis by the dissemination of circulating tumour cells (CTCs), highlights its importance as a targetable programme to combat cancer morbidity and mortality. Read More

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