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Journal of Biological Chemistry

Eva Horáková, Piya Changmai, Marie Vancová, Roman Sobotka, Jan Van Den Abbeele, Benoit Vanhollebeke, Julius Lukeš
The human parasite Trypanosoma brucei does not synthesize heme de novo and instead entirely relies on heme supplied by its vertebrate host or its insect vector, the tsetse fly. In the host bloodstream, T. brucei scavenges heme via haptoglobin-hemoglobin (HpHb) receptor-mediated endocytosis occurring in the flagellar pocket. However, in the procyclic developmental stage, in which T. brucei is confined to the tsetse fly midgut, this receptor is apparently not expressed, suggesting that T. brucei takes up heme by a different, unknown route...
February 23, 2017: Journal of Biological Chemistry
Giorgia De Franceschi, Chiara Fecchio, Ronit Sharon, Anthony H V Schapira, Christos Proukakis, Vittorio Bellotti, Patrizia Polverino de Laureto
α-Synuclein (aS) is a protein abundant in presynaptic nerve terminals in Parkinson disease (PD) and is a major component of intracellular Lewy bodies, the pathological hallmark of neurodegenerative disorders such as PD. Accordingly, the relationships between aS structure, its interaction with lipids, and its involvement in neurodegeneration have attracted great interest. Previously, we reported on the interaction of aS with brain polyunsaturated fatty acids, in particular docosahexaenoic acid (DHA). aS acquires an α-helical secondary structure in the presence of DHA and, in turn, affects DHA structural and aggregative properties...
February 23, 2017: Journal of Biological Chemistry
Xin Yang, Shiqi Yang, Chao Wang, Shihuan Kuang
Muscle satellite cells are myogenic stem cells whose quiescence, activation, self-renewal, and differentiation are influenced by oxygen supply, an environmental regulator of stem cell activity. Accordingly, stem cell-specific oxygen signaling pathways precisely control the balance between muscle growth and regeneration in response to oxygen fluctuations, and hypoxia-inducible factors (HIFs) are central mediators of these cellular responses. However, the in vivo roles of HIFs in quiescent satellite cells and activated satellite cells (myoblasts) are poorly understood...
February 23, 2017: Journal of Biological Chemistry
Jennifer A Groves, Austin O Maduka, Robert N O'Meally, Robert N Cole, Natasha E Zachara
The dynamic post-translational modification O-linked-β-N-acetylglucosamine (O-GlcNAc) regulates thousands of nuclear, cytoplasmic, and mitochondrial proteins. Cellular stress, including oxidative stress, results in increased O-GlcNAcylation of numerous proteins and this increase is thought to promote cell survival. The mechanisms by which the O-GlcNAc transferase (OGT) and the O-GlcNAcase (OGA), the enzymes that add and remove O-GlcNAc respectively, are regulated during oxidative stress to alter O-GlcNAcylation are not fully characterized...
February 23, 2017: Journal of Biological Chemistry
Yue Dai, Mohammad Mahfuzul Haque, Dennis J Stuehr
The signaling molecule nitric oxide (NO) is synthesized in animals by structurally related NO synthases (NOSs), which contain NADPH/FAD- and FMN-binding domains. During catalysis, NADPH-derived electrons transfer into FAD and then distribute into the FMN domain for further transfer to internal or external heme groups. Conformational freedom of the FMN domain is thought to be essential for the electron transfer (ET) reactions in NOSs. To directly examine this concept, we utilized a "Cys-lite" neuronal NOS flavoprotein domain and substituted Cys for two residues (Glu816 and Arg1229) forming a salt bridge between the NADPH/FAD and FMN domains in the conformationally closed structure to allow cross-domain disulfide bond formation or crosslinking by bismaleimides of various length...
February 23, 2017: Journal of Biological Chemistry
Wei Li, Hua Li, Liyuan Zhang, Min Hu, Fang Li, Jieqiong Deng, Mingxing An, Siqi Wu, Rui Ma, Jiachun Lu, Yifeng Zhou
Thousands of long intergenic non-protein coding RNAs (lincRNAs) have been identified in mammals in genome-wide sequencing studies. Some of these RNAs have been consistently conserved during the evolution of species and, could presumably function in important biological processes. We, therefore, measured the levels of 26 highly conserved lincRNAs in a total of 176 pairs of endometrial carcinoma (EC) and surrounding non-tumor tissues of two distinct Chinese populations. Here, we report that a lincRNA, LINC00672, which possesses an ultra-conserved region, is aberrantly downregulated during the development of EC...
February 23, 2017: Journal of Biological Chemistry
Cristina Landeta, Brian M Meehan, Laura McPartland, Linda Ingendahl, Feras Hatahet, Ngoc Q Tran, Dana Boyd, Jon Beckwith
Disulfide bonds contribute to protein stability, activity and folding in a variety of proteins including many involved in bacterial virulence such as, toxins, adhesins, flagella and pili among others. Therefore, inhibitors of disulfide bond formation enzymes could have profound effects on pathogen virulence. In the Escherichia coli disulfide bond formation pathway, the periplasmic protein DsbA introduces disulfide bonds into substrates and then the cytoplasmic membrane protein DsbB reoxidizes DsbAs cysteines regenerating its activity...
February 23, 2017: Journal of Biological Chemistry
Petra C Buchanan, Kristin L M Boylan, Bruce Walcheck, Rachel Heinze, Melissa A Geller, Peter A Argenta, Amy P N Skubitz
We previously showed that the cell adhesion molecule Nectin-4 is overexpressed in ovarian cancer tumors and its cleaved extracellular domain can be detected in the serum of ovarian cancer patients. The ADAM proteases (A Disintegrin and Metalloproteinase) are involved in ectodomain cleavage of transmembrane proteins and ADAM17 is known to cleave Nectin-4 in breast cancer. However, the mechanism of Nectin-4 cleavage in ovarian cancer has not yet been determined. Analysis of ovarian cancer gene microarray data showed that higher expression of Nectin-4, ADAM10, and ADAM17 is associated with significantly decreased progression-free survival...
February 23, 2017: Journal of Biological Chemistry
Steven Dajnowicz, Jerry M Parks, Xiche Hu, Korie Gesler, Andrey Y Kovalevsky, Timothy C Mueser
Pyridoxal 5'-phosphate (PLP) is a fundamental, multifunctional enzyme cofactor used to catalyze a wide variety of chemical reactions involved in amino acid metabolism. PLP-dependent enzymes optimize specific chemical reactions by modulating the electronic states of PLP through distinct active site environments. In asparate aminotransferase (AAT), an extended hydrogen-bond network is coupled to the pyridinyl nitrogen of the PLP, influencing the electrophilicity of the cofactor. This network, which involves residues D222, H143, T139, H189, and structural waters, is located at the edge of PLP opposite to the reactive Schiff base...
February 23, 2017: Journal of Biological Chemistry
Olga V Belyaeva, Mark K Adams, Lizhi Wu, Natalia Y Kedishvili
All-trans-retinoic acid (RA), a bioactive derivative of vitamin A, exhibits diverse effects on gene transcription and non-genomic regulatory pathways. The steady-state levels of RA are therefore tightly controlled, but the mechanisms responsible for RA homeostasis are not fully understood. We report a molecular mechanism that allows cells to maintain a stable rate of RA biosynthesis by utilizing a biological circuit generated by a bifunctional retinoid oxidoreductive complex (ROC). We show that ROC is composed of at least two subunits of NAD+-dependent retinol dehydrogenase 10 (RDH10), which catalyzes the oxidation of retinol to retinaldehyde, and two subunits of NADPH-dependent dehydrogenase reductase 3 (DHRS3), which catalyzes the reduction of retinaldehyde back to retinol...
February 22, 2017: Journal of Biological Chemistry
Jing Shi, Wei-Fei Chen, Bo Zhang, San-Hong Fan, Xia Ai, Na-Nv Liu, Stephane Rety, Xu-Guang Xi
Helicases play a critical role in processes such as replication or recombination by unwinding double-stranded DNA; mutations of these genes can therefore have devastating biological consequences. In human, mutations in genes of three members of the RecQ family helicases (blm, wrn and recq4) give rise to three strikingly distinctive clinical phenotypes: Bloom syndrome, Werner syndrome and Rothmund-Thomson syndrome, respectively. However, the molecular basis for these varying phenotypic outcomes is unclear, in part because a full mechanistic description of helicase activity is lacking...
February 22, 2017: Journal of Biological Chemistry
Yahong Wen, Grace Liao, Thomas Pritchard, Ting-Ting Zhao, Jon P Connelly, Shondra M Pruett-Miller, Valerie Blanc, Nicholas O Davidson, Blair B Madison
The discovery and application of CRISPR/Cas9 technology for genome editing has greatly accelerated targeted mutagenesis in a variety of organisms. CRISPR/Cas9-mediated site-specific cleavage is typically exploited for the generation of insertions or deletions (indels) following aberrant dsDNA repair via the endogenous non-homology end-joining (NHEJ) pathway, or alternatively, for enhancing homology directed repair (HDR) to facilitate the generation of a specific mutation (or knock-in). However, there is a need for efficient cellular assays that can measure Cas9/guide RNA (gRNA) activity...
February 22, 2017: Journal of Biological Chemistry
Sun Kyung Kim, Lindsey Barron, Cynthia S Hinck, Elyse M Petrunak, Kristin E Cano, Avinash Thangirala, Brian Iskra, Molly Brothers, Machell Vonberg, Belinda Leal, Blair Richter, Ravindra Kodali, Alex B Taylor, Shoucheng Du, Christopher O Barnes, Traian Sulea, Guillermo Calero, P John Hart, Matthew J Hart, Borries Demeler, Andrew P Hinck
The transforming growth factor beta isoforms, TGF-β1, -β2, and -β3 are small secreted homodimeric signaling proteins with essential roles in regulating the adaptive immune system and maintaining the extracellular matrix. However, dysregulation of the TGF-β pathway is responsible for promoting the progression of several human diseases, including cancer and fibrosis. In spite of the known importance of TGF-βs in promoting disease progression, no inhibitors have been approved for use in humans. Herein, we describe an engineered TGF-β monomer, lacking the heel helix, a structural motif essential for binding the TGF-β type I receptor, TβRI, but dispensible for binding the other receptor required for TGF-β signaling, the TGF-β type II receptor, TβRII, as an alternative therapeutic modality for blocking TGF-β signaling in humans...
February 22, 2017: Journal of Biological Chemistry
Zhuyan Guo, Stuart Black, Yuan Hu, Patricia McMonagle, Paul Ingravallo, Robert Chase, Stephanie Curry, Ernest Asante-Appiah
Grazoprevir is a potent pan-genotype, macrocyclic inhibitor of hepatitis C virus (HCV) NS3/4A protease and was developed for treating chronic HCV infection. In HCV genotype (GT) 1a, grazoprevir maintains potent activity against a majority of NS3 resistance-associated amino acid substitutions including the highly prevalent and naturally-occurring Q80K polymorphism that impacts simeprevir, another NS3/4A protease inhibitor. The basis for an unexpected difference in the clinical impact of some NS3 substitutions was investigated...
February 21, 2017: Journal of Biological Chemistry
Jing Qi, Ho-Jin Lee, Audrey Saquet, Xiao-Ning Cheng, Ming Shao, Jie J Zheng, De-Li Shi
Dishevelled (Dvl) is a key intracellular signaling molecule that mediates the activation of divergent Wnt pathways. It contains three highly conserved domains known as DIX, PDZ and DEP, whose functions in beta-catenin-dependent canonical Wnt and beta-catenin-independent non-canonical Wnt signaling have been well characterized. The C-terminal region is also highly conserved from invertebrates to vertebrates. However, its function in regulating the activation of different Wnt signals remains unclear. We previously reported that Dvl conformational change triggered by the highly conserved PDZ-binding C-terminus is important for the pathway specificity...
February 21, 2017: Journal of Biological Chemistry
Natalia Comino, Javier Cifuente, Alberto Marina, Ane Orrantia, Ander Eguskiza, Marcelo E Guerin
ADP-glucose pyrophosphorylase (AGPase) controls bacterial glycogen and plant starch biosynthetic pathways, the most common carbon storage polysaccharides in nature. AGPase activity is allosterically regulated by a series of metabolites in the energetic flux within the cell. Very recently, we reported the first crystal structures of the paradigmatic AGPase from Escherichia coli (EcAGPase) in complex with its preferred physiological negative and positive allosteric regulators, adenosine-5'-monophosphate (AMP) and fructose-1,6-bisphosphate (FBP), respectively...
February 21, 2017: Journal of Biological Chemistry
Vladimir Baytshtok, Jiejen Chen, Steven E Glynn, Andrew R Nager, Robert A Grant, Tania A Baker, Robert T Sauer
The HslUV proteolytic machine consists of HslV, a double-ring self-compartmentalized peptidase, and one or two AAA+ HslU ring hexamers that hydrolyze ATP to power the unfolding of protein substrates and their translocation into the proteolytic chamber of HslV. Here, we use genetic-tethering and disulfide-bonding strategies to construct HslU pseudohexamers containing mixtures of ATPase active and inactive subunits at defined positions in the hexameric ring. Genetic tethering impairs HslV binding and degradation, even for pseudohexamers with six active subunits, but disulfide-linked pseudohexamers do not have these defects, indicating that the peptide tether interferes with HslV interactions...
February 21, 2017: Journal of Biological Chemistry
Mathias Hohl, Annick Stintzi, Andreas Schaller
The propeptides of subtilisin-like serine proteinases (SBTs) serve dual functions as intramolecular chaperones that are required for enzyme folding and as inhibitors of the mature proteases. SBT propeptides are homologous to the I9 family of protease inhibitors that have only been described in fungi. Here we report the identification and characterization of Subtilisin Propeptide-Like Inhibitor 1 (SPI-1) from Arabidopsis thaliana. Sequence similarity and the shared β-α-β-β-α-β core structure identified SPI-1 as a member of the I9 inhibitor family, and as the first independent I9 inhibitor in higher eukaryotes...
February 21, 2017: Journal of Biological Chemistry
Yanli Liu, Su Qin, Ming Lei, Wolfram Tempel, Yuzhe Zhang, Peter Loppnau, Yanjun Li, Jinrong Min
Heterochromatin protein 1 (HP1), a highly conserved non-histone chromosomal protein in eukaryotes, plays important roles in the regulation of gene transcription. Each of the three human homologs of HP1 includes a chromoshadow domain (CSD). The CSD interacts with various proteins bearing the PxVxL motif, but also with a region of histone H3 that bears the similar PxxVxL motif. The latter interaction has not yet been resolved in atomic detail. Here we demonstrate that the CSDs of all three human HP1 homologs have comparable affinities to the PxxVxL motif of histone H3...
February 21, 2017: Journal of Biological Chemistry
Sotirios Gkekas, Ranjan Kumar Singh, Alexander V Shkumatov, Joris Messens, Maarten Fauvart, Natalie Verstraeten, Jan Michiels, Wim Versées
The Obg protein family belongs to the TRAFAC (translation factor) class of P-loop GTPases and is conserved from bacteria to eukaryotes. Essential roles in many different cellular processes have been suggested for the Obg protein from Escherichia coli (ObgE), and we recently showed that it is a central regulator of bacterial persistence. Here, we report the first crystal structure of ObgE at 1.85 Å resolution in the GDP-bound state, showing the characteristic N-terminal domain and a central G domain that are common to all Obg proteins...
February 21, 2017: Journal of Biological Chemistry
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