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Protein unfolding and translocation

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https://www.readbyqxmd.com/read/29652515/structure-and-function-of-the-26s-proteasome
#1
Jared A M Bard, Ellen A Goodall, Eric R Greene, Erik Jonsson, Ken C Dong, Andreas Martin
As the endpoint for the ubiquitin-proteasome system, the 26S proteasome is the principal proteolytic machine responsible for regulated protein degradation in eukaryotic cells. The proteasome's cellular functions range from general protein homeostasis and stress response to the control of vital processes such as cell division and signal transduction. To reliably process all the proteins presented to it in the complex cellular environment, the proteasome must combine high promiscuity with exceptional substrate selectivity...
April 13, 2018: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/29650257/neuropeptide-y-mitigates-er-stress-induced-neuronal-cell-death-by-activating-the-pi3k-xbp1-pathway
#2
Do Yeon Lee, Seung Hyun Hong, Bokyung Kim, Dong-Seok Lee, Kweon Yu, Kyu-Sun Lee
The unfolded protein response (UPR) is an evolutionarily conserved adaptive reaction that increases cell survival under endoplasmic reticulum (ER) stress conditions. ER stress-associated neuronal cell death pathways play roles in the pathogenesis of neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's disease. Neuropeptide Y (NPY) has an important role in neuroprotection against neurodegenerative diseases. In this study, we investigated whether NPY has a protective role in ER stress-induced neuronal cell death in SK-N-SH human neuroblastoma cells...
April 6, 2018: European Journal of Cell Biology
https://www.readbyqxmd.com/read/29626480/tspa-as-a-novel-atf6%C3%AE-translocation-inducer-efficiently-ameliorates-insulin-sensitivity-restoration-and-glucose-homeostasis-in-db-db-mice
#3
Tingting Zhou, Yanhua Cheng, Wenzhong Yan, Xiaofan Shi, Xin Xu, Jinpei Zhou, Jian Li, Jing Chen, Xu Shen
Activating transcription factor 6α (ATF6α) as a transducer in unfolded protein response (UPR), plays an important role in liver glucose metabolism and insulin resistance. Thus, targeting ATF6α activation has been proposed to be a potential strategy for anti-T2DM drug discovery. Here, we determined that small molecule 2-[5-[1-(4-chlorophenoxy)ethyl]-4-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)acetamide (TSPA) functioned as an ATF6α translocation inducer effectively promoting ATF6α translocation into nucleus and ameliorating glucose homeostasis on db/db mice...
April 4, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29626158/deubiquitinating-enzyme-usp9x-regulates-cellular-clock-function-by-modulating-the-ubiquitination-and-degradation-of-a-core-circadian-protein-bmal1
#4
Yang Zhang, Chunyan Duan, Jing Yang, Suping Chen, Qing Liu, Liang Zhou, Zhengyun Huang, Ying Xu, Guoqiang Xu
Living organisms on the earth maintain a roughly 24 h circadian rhythm, which is regulated by circadian clock genes as well as their protein products. Post-translational modifications of core clock proteins could affect the circadian behavior. Although ubiquitination of core clock proteins was studied extensively, the reverse process, deubiquitination, has only begun to unfold and the role of this regulation on circadian function is not completely understood. Here, we use affinity purification and mass spectrometry analysis to identify probable ubiquitin carboxyl-terminal hydrolase FAF-X (USP9X) as an interacting protein of the core clock protein aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL or BMAL1)...
April 6, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29603609/a-general-strategy-of-aerolysin-nanopore-detection-for-oligonucleotides-with-the-secondary-structure
#5
Dong-Fang Liao, Chan Cao, Yi-Lun Ying, Yi-Tao Long
An aerolysin nanopore is employed as a sensitive tool for single-molecule analysis of short oligonucleotides (≤10 nucleotides), poly(ethylene glycol) (PEGs), peptides, and proteins. However, the direct analysis of long oligonucleotides with the secondary structure (e.g., G-quadruplex topology) remains a challenge, which impedes the further practical applications of the aerolysin nanopore. Here, a simple and applicable method of aerolysin nanopore is presented to achieve a direct analysis of structured oligonucleotides that are extended to 30 nucleotides long by a cation-regulation mechanism...
March 30, 2018: Small
https://www.readbyqxmd.com/read/29595948/nanoporous-hydrogels-for-the-observation-of-anthrax-exotoxin-translocation-dynamics
#6
Christopher Baker, Ben Schudel, Mangesh I Chaudhari, Kerrie Wu, Derek Dunford, Anup K Singh, Susan B Rempe, Anson V Hatch
The ability to observe lethal anthrax exotoxins translocating through size-constricting nanopores in vitro, combined with detailed sequence and structural data, has aided in eluci- dated mechanisms of exotoxin cell entry and toxicity. However, due to limited observations of anthrax exotoxins translocating through protective antigen nanopores in vitro, and the instability of protective antigen-functionalized suspended lipid bilayers, questions remain re- garding the native mechanisms of cell entry. Nanoporous hydrogel membranes oer a robust tool for studying protein translocation with ensemble measurements that complement con- ventional single molecule translocation measurements...
March 29, 2018: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/29581854/ire1%C3%AE-xbp1-inhibitors-exerted-anti-tumor-activities-in-ewing-s-sarcoma
#7
Yu Tanabe, Yoshiyuki Suehara, Shinji Kohsaka, Takuo Hayashi, Keisuke Akaike, Kenta Mukaihara, Taisei Kurihara, Youngji Kim, Taketo Okubo, Midori Ishii, Saiko Kazuno, Kazuo Kaneko, Tsuyoshi Saito
Ewing's sarcoma (ES) is the second-most frequent pediatric bone tumor. Chromosomal translocation t(11;22)(q24:q12) results in the formation of EWS/FLI1 gene fusion, which is detected in approximately 90% of tumors of the Ewing family. Several transcriptome studies have provided lists of genes associated with EWS/FLI1 expression. However, the protein expression profiles associated with EWS/FLI1 have yet to be elucidated. In this study, to identify the regulated proteins associated with EWS/FLI1 and therapeutic targets in ES, we conducted proteomic studies using EWS/FLI1 knockdown in four Ewing's sarcoma cell lines and human mesenchymal stem cells (hMSCs) expressing EWS/FLI1...
March 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29570500/curcumin-mitigates-axonal-injury-and-neuronal-cell-apoptosis-through-the-perk-nrf2-signaling-pathway-following-diffuse-axonal-injury
#8
Tingqin Huang, Junjie Zhao, Dan Guo, Honggang Pang, Yonglin Zhao, Jinning Song
Diffuse axonal injury (DAI) accounts for more than 50% of all traumatic brain injury. In response to the mechanical damage associated with DAI, the abnormal proteins produced in the neurons and axons, namely, β-APP and p-tau, induce endoplasmic reticulum (ER) stress. Curcumin, a major component extracted from the rhizome of Curcuma longa, has shown potent anti-inflammatory, antioxidant, anti-infection, and antitumor activity in previous studies. Moreover, curcumin is an activator of nuclear factor-erythroid 2-related factor 2 (Nrf2) and promotes its nuclear translocation...
March 22, 2018: Neuroreport
https://www.readbyqxmd.com/read/29559557/probing-the-quality-control-mechanism-of-the-escherichia-coli-twin-arginine-translocase-with-folding-variants-of-a-de-novo-designed-heme-protein
#9
George A Sutherland, Katie J Grayson, Nathan B P Adams, Daphne M J Mermans, Alexander S Jones, Angus J Robertson, Dirk B Auman, Amanda A Brindley, Fabio Sterpone, Pierre Tuffery, Philippe Derreumaux, P Leslie Dutton, Colin Robinson, Andrew Hitchcock, C Neil Hunter
Protein transport across the cytoplasmic membrane of bacterial cells is mediated by either the general secretion (Sec) system or the twin arginine translocase (Tat). The Tat machinery exports folded and cofactor containing proteins from the cytoplasm to the periplasm by using the transmembrane proton motive force as a source of energy. The Tat apparatus apparently senses the folded state of its protein substrates, a quality control mechanism that prevents premature export of nascent unfolded or misfolded polypeptides, but its mechanistic basis has not yet been determined...
March 20, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29531812/modulation-of-nuclear-factor-kappa-b-activation-by-the-endoplasmic-reticulum-stress-sensor-perk-to-mediate-estrogen-induced-apoptosis-in-breast-cancer-cells
#10
Ping Fan, Amit K Tyagi, Fadeke A Agboke, Rohit Mathur, Niranjana Pokharel, V Craig Jordan
Stress responses are critical for estrogen (E2 )-induced apoptosis in E2 -deprived breast cancer cells. Nuclear factor-kappa B (NF-κB) is an important therapeutic target to prevent stress responses in chronic inflammatory diseases including cancer. However, whether E2 activates NF-κB to participate in stress-associated apoptosis in E2 -deprived breast cancer cells is unknown. Here, we demonstrated that E2 differentially modulates NF-κB activity according to treatment time. E2 initially has significant potential to suppress NF-κB activation; it completely blocks tumor necrosis factor alpha (TNFα)-induced activation of NF-κB...
December 2018: Cell Death Discovery
https://www.readbyqxmd.com/read/29488036/cholesterol-metabolism-physiological-regulation-and-pathophysiological-deregulation-by-the-endoplasmic-reticulum
#11
Clemens Röhrl, Herbert Stangl
Cholesterol is an essential lipid for mammalian cells and its homeostasis is tightly regulated. Disturbance of cellular cholesterol homeostasis is linked to atherosclerosis and cardiovascular diseases. A central role in the sensing and regulation of cholesterol homeostasis is attributed to the endoplasmic reticulum (ER). This organelle harbours inactive transcription factors, which sense ER cholesterol levels and initiate transcriptional responses after activation and translocation into the nucleus. Thereupon, these responses enable adaption to high or low cellular cholesterol levels...
February 27, 2018: Wiener Medizinische Wochenschrift
https://www.readbyqxmd.com/read/29478604/spinal-and-bulbar-muscular-atrophy
#12
Andrew P Lieberman
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset degenerative disorder of the neuromuscular system resulting in slowly progressive weakness and atrophy of the proximal limb and bulbar muscles. The disease is caused by the expansion of a CAG/glutamine tract in the amino-terminus of the androgen receptor. That SBMA exclusively affects males reflects the fact that critical pathogenic events are hormone-dependent. These include translocation of the polyglutamine androgen receptor from the cytoplasm to the nucleus and unfolding of the mutant protein...
2018: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/29433415/mechanical-protein-unfolding-and-degradation
#13
Adrian O Olivares, Tania A Baker, Robert T Sauer
AAA+ proteolytic machines use energy from ATP hydrolysis to degrade damaged, misfolded, or unneeded proteins. Protein degradation occurs within a barrel-shaped self-compartmentalized peptidase. Before protein substrates can enter this peptidase, they must be unfolded and then translocated through the axial pore of an AAA+ ring hexamer. An unstructured region of the protein substrate is initially engaged in the axial pore, and conformational changes in the ring, powered by ATP hydrolysis, generate a mechanical force that pulls on and denatures the substrate...
February 10, 2018: Annual Review of Physiology
https://www.readbyqxmd.com/read/29423676/heat-shock-transcriptional-factor-mediates-mitochondrial-unfolded-protein-response
#14
Naoki Koike, Yuuki Hatano, Takashi Ushimaru
For maintenance of cytoplasmic protein quality control (PQC), cytoplasmic heat shock proteins (HSPs) negatively control heat shock transcriptional factor (HSF) in a negative feedback loop. However, how mitochondrial protein quality control (mtPQC) is maintained is largely unknown. Here we present evidence that HSF directly monitors mtPQC in the budding yeast Saccharomyces cerevisiae. Mitochondrial HSP70 (Ssc1) negatively regulated HSF activity. Importantly, HSF was localized not only in the nucleus but also on mitochondria...
February 8, 2018: Current Genetics
https://www.readbyqxmd.com/read/29393572/tetracycline-alters-gene-expression-in-salmonella-strains-that-harbor-the-tn10-transposon
#15
M Hüttener, A Prieto, S Aznar, M Dietrich, S Paytubi, A Juárez
In this report we show that bacterial plasmids that harbor the Tn10 transposon (i.e., the IncHI1 plasmid R27) modify expression of different Salmonella regulons responding to the presence of tetracycline (Tc) in the medium. By using as a model the Tc-dependent upregulation of the ibpAB operon (which belongs to the heat shock regulon), we have identified Tn10- tetA (coding for a Tc efflux pump) and adjacent tetC sequences as required for ibpAB upregulation. Characterization of transcripts in the tetAC region showed that tetA transcription can continue into tetC sequences, generating a long 3'UTR sequence, which can protect transcripts from RNA processing, thus increasing expression of TetA protein...
February 2, 2018: Environmental Microbiology Reports
https://www.readbyqxmd.com/read/29369790/homeostatic-interplay-between-foxo-protein-and-er-proteostasis-in-cancer-and-other-diseases
#16
REVIEW
Matías González-Quiroz, Hery Urra, Celia María Limia, Claudio Hetz
Cancer cells are exposed to several adverse conditions within the tumor microenvironment that challenge cells to adapt and survive. Several of these homeostatic perturbations insults alter the normal function of the endoplasmic reticulum (ER), resulting in the accumulation of misfolded proteins. ER stress triggers a conserved signaling pathway known as the unfolded protein response (UPR) to cope with the stress or trigger apoptosis of damaged cells. The UPR has been described as a major driver of the acquisition of malignant characteristics that ultimately lead to tumor progression...
January 21, 2018: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29317503/er-stress-mobilization-of-death-associated-protein-kinase-1-dependent-xenophagy-counteracts-mitochondria-stress-induced-epithelial-barrier-dysfunction
#17
Fernando Lopes, Åsa V Keita, Alpana Saxena, Jose Luis Reyes, Nicole L Mancini, Ala Al Rajabi, Arthur Wang, Cristiane H Baggio, Michael Dicay, Rob van Dalen, Younghee Ahn, Matheus B H Carneiro, Nathan C Peters, Jong M Rho, Wallace K MacNaughton, Stephen E Girardin, Humberto Jijon, Dana J Philpott, Johan D Söderholm, Derek M McKay
The gut microbiome contributes to inflammatory bowel disease (IBD), in which bacteria can be present within the epithelium. Epithelial barrier function is decreased in IBD, and dysfunctional epithelial mitochondria and endoplasmic reticulum (ER) stress have been individually associated with IBD. We therefore hypothesized that the combination of ER and mitochondrial stresses significantly disrupt epithelial barrier function. Here, we treated human colonic biopsies, epithelial colonoids, and epithelial cells with an uncoupler of oxidative phosphorylation, dinitrophenol (DNP), with or without the ER stressor tunicamycin and assessed epithelial barrier function by monitoring internalization and translocation of commensal bacteria...
March 2, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29311273/translocation-through-the-conjugative-type-4-secretion-system-requires-unfolding-of-its-protein-substrate
#18
Martina Trokter, Gabriel Waksman
Bacterial conjugation, a mechanism of horizontal gene transfer, is the major means by which antibiotic resistance spreads among bacteria (1, 2). Conjugative plasmids are transferred from one bacterium to another through a type IV secretion system (T4SS) in a form of single-stranded DNA covalently attached to a protein called relaxase. The relaxase is fully functional both in a donor cell (prior to conjugation) and recipient cell (after conjugation). Here we demonstrate that the protein substrate has to unfold for efficient translocation through the conjugative T4SS...
January 8, 2018: Journal of Bacteriology
https://www.readbyqxmd.com/read/29208936/disulfide-driven-folding-for-a-conditionally-disordered-protein
#19
Hugo Fraga, Jordi Pujols, Marcos Gil-Garcia, Alicia Roque, Ganeko Bernardo-Seisdedos, Carlo Santambrogio, Joan-Josep Bech-Serra, Francesc Canals, Pau Bernadó, Rita Grandori, Oscar Millet, Salvador Ventura
Conditionally disordered proteins are either ordered or disordered depending on the environmental context. The substrates of the mitochondrial intermembrane space (IMS) oxidoreductase Mia40 are synthesized on cytosolic ribosomes and diffuse as intrinsically disordered proteins to the IMS, where they fold into their functional conformations; behaving thus as conditionally disordered proteins. It is not clear how the sequences of these polypeptides encode at the same time for their ability to adopt a folded structure and to remain unfolded...
December 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29180014/structural-insights-into-the-oligomerization-of-ftsh-periplasmic-domain-from-thermotoga-maritima
#20
Jun Yop An, Humayun Sharif, Gil Bu Kang, Kyung Jin Park, Jung-Gyu Lee, Sukyeong Lee, Mi Sun Jin, Ji-Joon Song, Jimin Wang, Soo Hyun Eom
Prompt removal of misfolded membrane proteins and misassembled membrane protein complexes is essential for membrane homeostasis. However, the elimination of these toxic proteins from the hydrophobic membrane environment has high energetic barriers. The transmembrane protein, FtsH, is the only known ATP-dependent protease responsible for this task. The mechanisms by which FtsH recognizes, unfolds, translocates, and proteolyzes its substrates remain unclear. The structure and function of the ATPase and protease domains of FtsH have been previously characterized while the role of the FtsH periplasmic domain has not clearly identified...
January 1, 2018: Biochemical and Biophysical Research Communications
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