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Biochemical Journal

Yan Li, Shuang Liu, Elizabeth Yihui Ng, Rong Li, Anders Poulsen, Jeffrey Hill, Ajaybabu V Pobatti, Alvin W Hung, Wanjin Hong, Thomas H Keller, CongBao Kang
The oncoprotein YAP requires the TEAD family of transcription factors for the upregulation of genes important for cell proliferation. Disrupting YAP-TEAD interaction is an attractive strategy for cancer therapy. Targeting TEADs using small molecules that either bind to the YAP-binding pocket or the palmitate-binding pocket is proposed to the disrupt YAP-TEAD interaction. There is a need for methodologies to facilitate robust and reliable identification of compounds that occupy either YAP-binding pocket or palmitate-binding pocket...
May 14, 2018: Biochemical Journal
Jiamiao Hu, Si Kee Tan, Michelle Gek Liang Lim, Shie Hong Chang, Guimei Cui, Shanshan Liu, Kamesh Narasimhan, Siu Yee New, Xuecong Wang, Congling Chen, Harapriya Chakravarty, Prasanna R Kolatkar, Kin Yip Tam, Qian Lu, Xiaodi Su, Ralf Jauch, Edwin Cheung
AP-2 gamma (AP-2γ) is a transcription factor that plays pivotal roles in breast cancer biology. To search for small molecule inhibitors of AP-2γ, we performed a high-throughput fluorescence anisotropy screen and identified a polyoxometalate compound with Wells-Dawson structure K6 [P2 Mo18 O62 ] (Dawson-POM) that blocks the DNA binding activity of AP-2γ. We showed this blocking activity is due to the direct binding of Dawson-POM to AP-2γ. We also provide evidence to show that Dawson-POM decreases AP-2γ dependent transcription similar to silencing the gene...
May 14, 2018: Biochemical Journal
Min-Kyu Kwak, Han-Bong Ryu, Sung-Hyun Song, Jin-Won Lee, Sa-Ouk Kang
YlaD, a membrane-anchored anti-sigma factor of Bacillus subtilis , contains a HX3 CXXC motif that functions as a redox-sensing domain and belongs to one of the zinc-coordinated anti-sigma factor families. Despite previously showing that the YlaC transcription is controlled by YlaD, experimental evidence of how the YlaC-YlaD interaction is affected by active cysteines and/or metal ions is lacking. Here, we showed that the P yla promoter is autoregulated solely by YlaC. Moreover, reduced YlaD contained zinc and iron, while oxidized YlaD did not...
May 14, 2018: Biochemical Journal
Meng Yuan, Iain W McNae, Yiyuan Chen, Elizabeth A Blackburn, Martin A Wear, Paul A M Michels, Linda A Fothergill-Gilmore, Ted Hupp, Malcolm D Walkinshaw
We have tested the effect of all 20 proteinogenic amino acids on the activity of the M2 isoenzyme of pyruvate kinase (M2PYK) and show that within physiologically relevant concentrations, phenylalanine, alanine, tryptophan, methionine, valine, and proline act as inhibitors while histidine and serine act as activators. Size exclusion chromatography has been used to show that all amino acids, whether activators or inhibitors, stabilise the tetrameric form of M2PYK. In the absence of amino-acid ligands an apparent tetramer-monomer dissociation K d is estimated to be ~0...
May 10, 2018: Biochemical Journal
Ioannis Dafnis, Christina Raftopoulou, Christina Mountaki, Evgenia Megalou, Vassilis I Zannis, Angeliki Chroni
The beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates the production of amyloid-beta peptide (Aβ) which is central to the pathogenesis of Alzheimer's disease (AD). Changes in brain cholesterol homeostasis have been suggested to affect Aβ metabolism. Cholesterol homeostasis is maintained in the brain by apolipoprotein E (apoE). The apoE4 isoform constitutes the major risk factor for AD. Here, we investigated the effect of apoE forms on Aβ generation and on BACE1 levels. We also examined the potential involvement in these processes of cholesterol transporters ABCG1 and ABCG4 or the lipoprotein receptor SR-BI that are implicated in cholesterol efflux to apoE...
May 9, 2018: Biochemical Journal
Rafeeq Mir, Francesca Tonelli, Pawel Lis, Thomas Macartney, Nicole K Polinski, Terina N Martinez, Meng-Yun Chou, Andrew J M Howden, Theresa König, Christoph Hotzy, Ivan Milenkovic, Thomas Brücke, Alexander Zimprich, Esther Sammler, Dario R Alessi
Missense mutations in the LRRK2 and VPS35 genes result in autosomal dominant Parkinson's disease. The VPS35 gene encodes for the cargo-binding component of the retromer complex, while LRRK2 modulates vesicular trafficking by phosphorylating a subgroup of Rab proteins. Pathogenic mutations in LRRK2 increase its kinase activity. It is not known how the only thus far described pathogenic VPS35 mutation, [D620N] exerts its effects. We reveal that the VPS35[D620N] knock-in mutation, strikingly elevates LRRK2 mediated phosphorylation of Rab8A, Rab10 and Rab12 in mouse embryonic fibroblasts...
May 9, 2018: Biochemical Journal
Meenu R Rajan, Elin Nyman, Cecilia Brännmark, Charlotta S Olofsson, Peter Strålfors
Type 2 diabetes is characterized by insulin resistance in the expanding adipose tissue of obesity. The insulin resistance manifests in human adipocytes as system-wide impairment of insulin signalling. An exception is regulation of transcription factor FOXO1, which is phosphorylated downstream of mTORC2 and is therefore not exhibiting impaired response to insulin. However, the abundance, and activity, of FOXO1 is reduced by half in adipocytes from patients with diabetes. To elucidate the effect of reduced FOXO1 activity, we herein transduced human adipocytes with a dominant-negative construct of FOXO1 (DN-FOXO1)...
May 3, 2018: Biochemical Journal
Andreas Sukmana, Zhaomin Yang
The bacterial type IV pilus (T4P) is a versatile nanomachine that functions in pathogenesis, biofilm formation, motility, and horizontal gene transfer. T4P assembly is powered by the motor ATPase PilB which is proposed to hydrolyze ATP by a symmetrical rotary mechanism. This mechanism, which is deduced from the structure of PilB, is untested. Here, we report the first kinetic studies of the PilB ATPase, supporting coordination among the protomers of this hexameric enzyme. Analysis of the genome sequence of Chloracidobacterium thermophilum identified a pilB gene whose protein we then heterologously expressed...
May 1, 2018: Biochemical Journal
Maike K Groenewold, Marco Massmig, Stefanie Hebecker, Linna Danne, Zofia Magnowska, Manfred Nimtz, Franz Narberhaus, Dieter Jahn, Dirk W Heinz, Lothar Jänsch, Jürgen Moser
A quantitative Pseudomonas aeruginosa proteomics approach revealed increased abundance of the so far uncharacterized protein PA3911 in anaerobic biofilms grown under conditions of the cystic fibrosis lung. Physiological relevance of ORF PA3911 was demonstrated, inter alia , using phenotype microarray experiments. The mutant strain showed increased susceptibility in the presence of antimicrobials (minocycline, nafcillin, oxacillin, chloramphenicol, thiamphenicol), enhanced twitching motility and significantly impaired biofilm formation...
May 1, 2018: Biochemical Journal
Joern Krausze, Thomas W Hercher, Dagmar Zwerschke, Martin L Kirk, Wulf Blankenfeldt, Ralf R Mendel, Tobias Kruse
The molybdenum cofactor (Moco) is a redox-active prosthetic group found in the active site of Moco- dependent enzymes, which are vitally important for life. Moco biosynthesis involves several enzymes that catalyze the subsequent conversion of GTP to cyclic pyranopterin monophoshpate (cPMP), molybdopterin (MPT), adenylated MPT (MPT-AMP) and finally Moco. While the underlying principles of cPMP, MPT, and MPT-AMP formation are well-understood, the molybdenum insertase (Mo-insertase) catalyzed final Moco maturation step is not...
May 1, 2018: Biochemical Journal
Makoto Kurano, Hitoshi Ikeda, Naoyuki Iso-O, Masumi Hara, Kazuhisa Tsukamoto, Yutaka Yatomi
Apolipoprotein M (apoM) is a carrier and a modulator of sphingosine 1-phosphate (S1P), an important multi-functional bioactive lipid. Since PPARγ is reportedly associated with the function and metabolism of S1P, we investigated the modulation of apoM/S1P homeostasis by PPARγ. First, we investigated the modulation of apoM and S1P homeostasis by the overexpression or knockdown of PPARγ in HepG2 cells and found that both the overexpression and the knockdown of PPARγ decreased apoM expression and S1P synthesis...
April 30, 2018: Biochemical Journal
Vijay Kumar, Amresh Prakash, Preeti Pandey, Andrew M Lynn, Md Imtaiyaz Hassan
Misfolding and aggregation of Cu, Zn Superoxide dismutase (SOD1) is involved in the neurodegenerative disease, amyotrophic lateral sclerosis (ALS). Many studies have shown that metal depleted, monomeric form of SOD1 displays substantial local unfolding dynamics and is the precursor for aggregation. Here we have studied the structure and dynamics of different apo monomeric SOD1 variants associated with unfolding and aggregation in aqueous trifluoroethanol (TFE) through experiments and simulation. TFE induces partially unfolded β-sheet-rich extended conformations in these SOD1 variants, which subsequently develops aggregates with fibril like characteristics...
April 23, 2018: Biochemical Journal
Ditlev Birch, Malene V Christensen, Dan Staerk, Henrik Franzyk, Hanne M Nielsen
Cell-penetrating peptides (CPPs) comprise efficient peptide-based delivery vectors. Due to the inherent poor enzymatic stability of peptides, CPPs displaying partial or full replacement of L-amino acids with the corresponding D-amino acids might possess advantages as delivery vectors. Thus, the present study aims to elucidate the membrane- and metabolism-associated effects of L-Penetratin (L-PEN) and its corresponding all-D analogue (D-PEN). These effects were investigated when exerted on hepatocellular (HepG2) or intestinal (Caco-2, IEC-6) cell culture models...
April 23, 2018: Biochemical Journal
Virginia Actis Dato, Rubén A Grosso, María C Sánchez, Claudio M Fader, Gustavo A Chiabrando
Low-density lipoprotein (LDL) receptor-related protein-1 (LRP1) is expressed in retinal Müller glial cells (MGCs) and regulates intracellular translocation to the plasma membrane (PM) of the membrane proteins involved in cellular motility and activity. Different functions of MGCs may be influenced by insulin, including the removal of extracellular glutamate in the retina. In the present work, we investigated whether insulin promotes LRP1 translocation to the PM in the Müller glial-derived cell line MIO-M1...
April 18, 2018: Biochemical Journal
Eunjin Koh, Young Kyung Kim, Daye Shin, Kyung-Sup Kim
Mitochondrial pyruvate carrier (MPC), which is essential for mitochondrial pyruvate usage, mediates transport of cytosolic pyruvate into mitochondria. Low MPC expression is associated with various cancers, and functionally associated with glycolytic metabolism and stemness. However, the mechanism by which MPC expression is regulated is largely unknown. In this study, we showed that MPC1 is downregulated in human renal cell carcinoma (RCC) due to strong suppression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1 alpha (PGC-1α)...
April 18, 2018: Biochemical Journal
Megan H Cox, Parth Kapoor, Deborah A Briggs, Ian D Kerr
Multidrug binding and transport by the ATP binding cassette transporter ABCG2 is a factor in the clinical resistance to chemotherapy in leukaemia, and a contributory factor to the pharmacokinetic profiles of many other prescribed drugs. Despite its importance, the structural basis of multidrug transport, i.e. the ability to transport multiple distinct chemicals, has remained elusive. Previous research has shown that at least two residues positioned towards the cytoplasmic end of transmembrane helix 3 (TM3) of the transporter play a role in drug transport...
April 16, 2018: Biochemical Journal
Chandraditya Chakraborty, Sraboni Mitra, Anirban Roychowdhury, Sudip Samadder, Sankhadeep Dutta, Anup Roy, Pradip Das, Ranajit Kumar Mandal, Tyson V Sharp, Susanta Roychoudhury, Chinmay Kumar Panda
To understand the mechanism of cellular stress in basal-parabasal layers of normal-cervix and during different stages of cervical carcinoma, we analyzed the alterations (expression/methylation/copy-number variation/mutation) of HIF-1α and its associated genes LIMD1, VHL and VEGF in disease free normal-cervix (n=9), adjacent normal-cervix of tumors (n=70), CIN (n=32), CACX (n=174) samples and two CACX cell lines. In basal-parabasal layers of normal-cervix, LIMD1 showed high protein-expression while low protein expression of VHL was concordant with high expression of HIF-1α and VEGF irrespective of HPV16 infection...
April 13, 2018: Biochemical Journal
Tyler Duellman, Xi Chen, Rie Wakamiya, Jay Yang
Matrix metalloproteinases play varied roles in normal biology and diseases where, depending on the context, both inhibition and enhancement of the enzymatic activity may be beneficial. However, there are very few reports of positive modulators of MMP activity. We report that polynucleotides, including single stranded DNA, RNA, and even double stranded DNA bind to and enhance the enzymatic activity of MMP9. This enhancement of MMP9 catalytic activity is not shared by biologically-active poly-cationic molecules suggesting non-specific charge screening as an unlikely mechanism...
April 13, 2018: Biochemical Journal
Leena Rauhala, Tiina Jokela, Riikka Kärnä, Geneviève Bart, Piia Takabe, Sanna Oikari, Markku I Tammi, Sanna Pasonen-Seppänen, Raija H Tammi
Extracellular nucleotides are used as signaling molecules by several cell types. In epidermis, their release is triggered by insults such as ultraviolet radiation, barrier disruption and wounding and by specific nerve terminals firing. Increased synthesis of hyaluronan, a ubiquitous extracellular matrix glycosaminoglycan, also occurs in response to stress, leading to the attractive hypothesis that nucleotide signaling and hyaluronan synthesis could also be linked. In HaCaT keratinocytes ATP caused a rapid and strong but transient activation of hyaluronan synthase 2 ( HAS2 ) expression via PKC-, CaMKII-, MAPK- and CREB-dependent pathways by activating the purinergic P2Y2 receptor...
April 6, 2018: Biochemical Journal
Ying Liu, Xin Gao, Yi Miao, Yuanyuan Wang, Huan Wang, Rui Zhang, Zhe Cheng, Xi Wang, Xiaogang Jing, Liuqun Jia, Lingling Dai, Meng Liu, Lin An
Activation of nucleotide binding oligomerization domain (Nod)-like receptor (NLR) protein 3 (NLRP3) inflammasome received substantial attention recently in inflammatory diseases. Macrophages contribute to allergic inflammation in asthma. This study was aimed to investigate the effect of NLRP3 inflammasome on the polarization of macrophages. We utilized human primary monocytes and monocyte-derived macrophages to study expression of NLRP3 inflammasome components (NLRP3, ASC, caspase-1) and its downstream cytokine interleukin-1β (IL-1β)...
April 6, 2018: Biochemical Journal
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