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Journal of Biological Chemistry

Chun-Liang Chen, James C Mermoud, Lake N Paul, Calvin Nicklaus Steussy, Cynthia V Stauffacher
The mevalonate pathway produces isopentenyl diphosphate (IPP), a building block for polyisoprenoid synthesis, and is a crucial pathway for growth of the human bacterial pathogen Enterococcus faecalis. The final enzyme in this pathway, mevalonate diphosphate decarboxylase (MDD), acts on mevalonate diphosphate (MVAPP) to produce IPP while consuming ATP. This essential enzyme has been suggested as a therapeutic target for the treatment of drug-resistant bacterial infections. Here we report functional and structural studies on the mevalonate diphosphate decarboxylase from E...
October 12, 2017: Journal of Biological Chemistry
Shinya Ito, Koji Ogawa, Koh Takeuchi, Motoki Takagi, Masahito Yoshida, Takatsugu Hirokawa, Shoshiro Hirayama, Kazuo Shin-Ya, Ichio Shimada, Takayuki Doi, Naoki Goshima, Tohru Natsume, Kazuhiro Nagata
Fibrosis can disrupt tissue structure and integrity and impair organ function. Fibrosis is characterized by abnormal collagen accumulation in the extracellular matrix. Pharmacological inhibition of collagen secretion therefore represents a promising strategy for the management of fibrotic disorders, such as liver and lung fibrosis. Hsp47 is an endoplasmic reticulum (ER)-resident collagen-specific molecular chaperone essential for correct folding of procollagen in the ER. Genetic deletion of Hsp47 or inhibition of its interaction with procollagen interferes with procollagen triple helix production, which vastly reduces procollagen secretion from fibroblasts...
October 12, 2017: Journal of Biological Chemistry
Rebecca L Williamson, Karine Laulagnier, André Miguel Miranda, Marty A Fernandez, Michael S Wolfe, Rémy Sadoul, Gilbert Di Paolo
Amyloid plaques, a neuropathological hallmark 1 of Alzheimer's disease (AD), are largely 2 composed of amyloid beta (Aβ) peptide, derived 3 from cleavage of amyloid precursor protein 4 (APP) by β- and γ-secretases. The endosome is 5 increasingly recognized as an important 6 crossroad for APP and these secretases, with 7 major implications for APP processing and 8 amyloidogenesis. Among various 9 posttranslational modifications affecting APP 10 accumulation, ubiquitination of cytodomain 11 lysines may represent a key signal controlling 12 APP endosomal sorting...
October 11, 2017: Journal of Biological Chemistry
Jeffrey S Rush, Rebecca J Edgar, Pan Deng, Jing Chen, Haining Zhu, Nina M van Sorge, Andrew J Morris, Konstantin V Korotkov, Natalia Korotkova
In many Lactobacillales species (i.e. lactic acid bacteria), peptidoglycan is decorated by polyrhamnose polysaccharides that are critical for cell envelope integrity and cell shape and also represent key antigenic determinants. Despite the biological importance of these polysaccharides, their biosynthetic pathways have received limited attention. The important human pathogen, Streptococcus pyogenes, synthesizes a key antigenic surface polymer-the Lancefield group A carbohydrate (GAC). GAC is covalently attached to peptidoglycan and consists of a polyrhamnose polymer, with N-acetylglucosamine (GlcNAc) side chains, which is an essential virulence determinant...
October 11, 2017: Journal of Biological Chemistry
Zhe Li, Xueyan Li, Shanshan Nai, Qizhi Geng, Ji Liao, Xingzhi Xu, Jing Li
Checkpoint kinase 1 (Chk1) is a kinase instrumental for orchestrating DNA replication, DNA damage checkpoints, the spindle assembly checkpoint and cytokinesis. Despite Chk1's pivotal role in multiple cellular processes, many of its substrates remain elusive. Here, we identified O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) as one of Chk1's substrates. We found that Chk1 interacts with and phosphorylates OGT at Ser-20, which not only stabilizes OGT, but also is required for cytokinesis. Phospho-specific antibodies of OGT-pSer-20 exhibited specific signals at the midbody of the cell, consistent with midbody localization of OGT as previously reported...
October 11, 2017: Journal of Biological Chemistry
Melissa W Li, Arthur C Sletten, Jiyeon Lee, Kelly D Pyles, Scot J Matkovich, Daniel S Ory, Jean E Schaffer
Small nucleolar RNAs (snoRNAs) guide chemical modifications of ribosomal and small nuclear RNAs, functions that are carried out in the nucleus. While most snoRNAs reside in the nucleolus, a growing body of evidence indicates that snoRNAs are also present in the cytoplasm and that snoRNAs move between the nucleus and cytoplasm by a mechanism that is regulated by lipotoxic and oxidative stress. Here, in a genome-wide shRNA-based screen we identified nuclear export factor 3 (NXF3) as a transporter that alters the nucleocytoplasmic distribution of box C/D snoRNAs from the ribosomal protein L13a (Rpl13a) locus...
October 11, 2017: Journal of Biological Chemistry
Michael A Casasanta, Christopher C Yoo, Hans B Smith, Alison J Duncan, Kyla Cochrane, Ann C Varano, Emma Allen-Vercoe, Daniel J Slade
Fusobacterium nucleatum is an oral pathogen that is linked to multiple human infections and colorectal cancer. Strikingly, F. nucleatum achieves virulence in the absence of large, multi-protein secretion systems (Type I, II, III, IV, and VI) which are widely used by Gram-negative bacteria for pathogenesis. By contrast, F. nucleatum strains contain genomic expansions of Type V secreted effectors (autotransporters) that are critical for host cell adherence, invasion, and biofilm formation. Here we present the first characterization of a F...
October 11, 2017: Journal of Biological Chemistry
Andy van Hateren, Malcolm Anderson, Alistair Bailey, Jörn M Werner, Paul J Skipp, Tim Elliott
Major histocompatibility complex class I molecules (MHC I) help protect jawed vertebrates by binding and presenting immunogenic peptides to cytotoxic T lymphocytes. Peptides are selected from a large diversity present in the endoplasmic reticulum. However, only a limited number of peptides complement the polymorphic MHC specificity determining pockets in a way that leads to high affinity peptide binding and efficient antigen presentation. MHC I molecules possess an intrinsic ability to discriminate between peptides, which varies in efficiency between allotypes, but the mechanism of selection is unknown...
October 11, 2017: Journal of Biological Chemistry
Hema M Swasthi, Samrat Mukhopadhyay
Curli is a functional amyloid protein in the extracellular matrix of enteric Gram-negative bacteria. Curli is assembled at the cell surface and consists of CsgA, the major subunit of curli, and a membrane-associated nucleator protein, CsgB. Oligomeric intermediates that accumulate during the lag phase of amyloidogenesis are generally toxic, but the underlying mechanism by which bacterial cells overcome this toxicity during curli assembly at the surface remains elusive. Here, we elucidated the mechanism of curli amyloidogenesis and provide molecular insights into the strategy by which bacteria can potentially bypass the detrimental consequences of toxic amyloid intermediates...
October 11, 2017: Journal of Biological Chemistry
Ilaria Dalla Rosa, Hongliang Zhang, Salim Khiati, Xiaolin Wu, Yves Pommier
Mitochondrial DNA (mtDNA) is essential for cell viability because it encodes subunits of the respiratory chain complexes. Mitochondrial topoisomerase IB (TOP1MT) facilitates mtDNA replication by removing DNA topological tensions produced during mtDNA transcription, but appears to be dispensable. To test whether cells lacking TOP1MT have aberrant mtDNA transcription, we performed mitochondrial transcriptome profiling. To that end, we designed and implemented a customized tiling array, which enabled genome-wide, strand-specific, and simultaneous detection of all mitochondrial transcripts...
October 11, 2017: Journal of Biological Chemistry
Yanyan Tian, Xi Shen, Rui Wang, Naeh Klages-Mundt, Erica J Lynn, Sara K Martin, Yin Ye, Min Gao, Junjie Chen, Katharina Schlacher, Lei Li
In response to DNA crosslinking damage, the Fanconi anemia (FA) core complex activates the FA pathway by monoubiquitinating Fanconi anemia complementation group D2 (FANCD2) for the initiation of the nucleolytic processing of the DNA crosslinks and stabilization of stalled replication forks. Given that all the classic FA proteins coordinately monoubiquitinate FANCD2, it is unclear why losses of individual classic FA genes yield varying cellular sensitivities to crosslinking damage. To address this question, we generated cellular knockout models of FA core complex components and FANCD2 and found that FANCD2-null mutants display higher levels of spontaneous chromosomal damage and hypersensitivity to replication-blocking lesions than Fanconi anemia complementation group L (FANCL)-null mutants, suggesting that FANCD2 provides a basal level of DNA protection countering endogenous lesions in the absence of monoubiquitination...
October 11, 2017: Journal of Biological Chemistry
Granton A Jindal, Yogesh Goyal, John M Humphreys, Eyan Yeung, Kaijia Tian, Victoria L Patterson, Haixia He, Rebecca D Burdine, Stanislav Y Shvartsman, Elizabeth J Goldsmith
The MEK1 kinase directly phosphorylates ERK2, after the activation loop of MEK1 is itself phosphorylated by Raf. Studies over the past decade have revealed a large number of disease-related mutations in the MEK1 gene that lead to tumorigenesis and abnormal development. Several of these mutations result in MEK1 constitutive activity, but how they affect MEK1 regulation and function remains largely unknown. Here, we address these questions focusing on two pathogenic variants of the Phe-53 residue, which maps to the well-characterized negative regulatory region of MEK1...
October 10, 2017: Journal of Biological Chemistry
Maria E Zoghbi, Leo Mok, Douglas J Swartz, Anukriti Singh, Gregory A Fendley, Ina L Urbatsch, Guillermo A Altenberg
P-glycoprotein (Pgp) is an efflux pump important in multidrug resistance of cancer cells and in determining drug pharmacokinetics. Pgp is a prototype ATP-binding cassette (ABC) transporter with two nucleotide-binding domains (NBDs) that bind and hydrolyze ATP. Conformational changes at the NBDs (the Pgp engines) lead to changes across Pgp transmembrane domains that result in substrate translocation. According to current alternating access models (substrate binding pocket accessible only to one side of the membrane at a time) binding of ATP promotes NBD dimerization, resulting in external accessibility of the drug-binding site (outward-facing, closed NBD conformation), and ATP-hydrolysis leads to dissociation of the NBDs with the subsequent return of the accessibility of the binding site to the cytoplasmic side (inward-facing, open NBD conformation)...
October 9, 2017: Journal of Biological Chemistry
Inga Nilsson, Kerri Grove, Dustin Dovala, Tsuyoshi Uehara, Guillaume Lapointe, David A Six
3-Deoxy-D-manno-oct-2-ulosonic acid (Kdo) is an essential component of LPS in the outer leaflet of the Gram-negative bacterial outer membrane. While labeling of Escherichia coli with the chemical reporter 8-azido-3,8-dideoxy-D-manno-oct-2-ulosonic acid (Kdo-N3) has been reported, its incorporation into LPS has not been directly shown. We have now verified Kdo-N3 incorporation into E. coli LPS at the molecular level. Using PAGE analysis, we show that Kdo-N3 is localized to the outer membrane and specifically incorporates into rough and deep-rough LPS...
October 9, 2017: Journal of Biological Chemistry
Yuichi Kitai, Masashi Iwakami, Kodai Saitoh, Sumihito Togi, Serina Isayama, Yuichi Sekine, Ryuta Muromoto, Jun-Ichi Kashiwakura, Akihiko Yoshimura, Kenji Oritani, Tadashi Matsuda
Signal-transducing adaptor family member-2 (STAP-2) is an adaptor protein that regulates various intracellular signaling pathways and promotes tumorigenesis in melanoma and breast cancer cells. However, the contribution of STAP-2 to the behavior of other types of cancer cells is unclear. Here, we show that STAP-2 promotes tumorigenesis of prostate cancer cells through upregulation of EGFR signaling. Tumor growth of a prostate cancer cell line, DU145, was strongly decreased by STAP-2 knockdown. EGF-induced gene expression and phosphorylation of AKT, ERK, and STAT3 were significantly decreased in STAP-2-knockdown DU145 cells...
October 6, 2017: Journal of Biological Chemistry
Ogun Adebali, Aziz Sancar, Christopher P Selby
Nucleotide excision repair in E. coli is stimulated by transcription, specifically in the transcribed strand (TS). Previously, it was shown that this transcription-coupled repair (TCR) is mediated by the Mfd translocase. Recently, it was proposed that in fact the majority of TCR in E. coli is catalyzed by a second pathway ('backtracking-mediated TCR') that is dependent on the UvrD helicase and the ppGpp alarmone/stringent response regulator. Recently, we reported that as measured by the Excision Repair-Sequencing XR-seq), UvrD plays no role in TCR genome-wide...
October 6, 2017: Journal of Biological Chemistry
Robert H Wilson, Elena Martin-Avila, Carly Conlan, Spencer M Whitney
An overarching goal of photosynthesis research is to identify how components of the process can be improved to benefit crop productivity, global food security and renewable energy storage. Improving carbon fixation has mostly focused on enhancing the CO2 fixing enzyme Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). This grand challenge has mostly proved ineffective due to catalytic mechanism constraints and required chaperone complementarity that hinder Rubisco biogenesis in alternative hosts. Here we refashion Escherichia coli metabolism by expressing a phosphoribulokinase-neomycin phosphotransferase fusion protein to produce a high fidelity, high throughput Rubisco directed evolution (RDE2) screen that negates false positive selection...
October 6, 2017: Journal of Biological Chemistry
Gloria Esteso, Susana Guerra, Mar Valés-Gómez, Hugh T Reyburn
Self/non-self discrimination by the innate immune system relies on germline-encoded, non-rearranging receptors expressed by innate immune cells recognizing conserved pathogen-associated molecular patterns. The natural killer group 2D (NKG2D) receptor is a potent immune-activating receptor that binds human genome-encoded ligands, whose expression is negligible in normal tissues, but increased in stress and disease conditions for reasons that are incompletely understood. Here it is not clear how the immune system reconciles receptor binding of self-proteins with self/non-self discrimination to avoid autoreactivity...
October 6, 2017: Journal of Biological Chemistry
Tithi Banerjee, Zeliang Zheng, Jane Abolafia, Shelby Harper, Donald B Oliver
The bacterial Sec-dependent system is the major protein-biogenic pathway for protein secretion across the cytoplasmic membrane or insertion of integral membrane proteins into the phospholipid bilayer. The mechanism of SecA-driven protein transport across the SecYEG channel complex has remained controversial with conflicting claims from biochemical and structural studies regarding the depth and extent of SecA insertion into SecYEG during ongoing protein transport. Here we utilized site-specific in vivo photo-crosslinking to thoroughly map SecY regions that are in contact with SecA during its insertion cycle...
October 6, 2017: Journal of Biological Chemistry
Brian Skriver Nielsen, Jette Skov Alstrom, Bruce Nicholson, Morten Schak Nielsen, Nanna MacAulay
Gap junctions confer interconnectivity of the cytoplasm in neighboring cells via docking of two connexons expressed in each of the adjacent membranes. Undocked connexons, referred to as hemichannels, may open and connect the cytoplasm with the extracellular fluid. The hemichannel configuration of connexins (Cxs) displays isoform-specific permeability profiles that are not directly determined by the size and charge of the permeant. To further explore Ca(2+)-mediated gating and permeability features of connexin hemichannels, we heterologously expressed Cx30 hemichannels in Xenopus laevis oocytes...
October 5, 2017: Journal of Biological Chemistry
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