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https://www.readbyqxmd.com/read/29754956/measuring-endoplasmic-reticulum-signal-sequences-translocation-efficiency-using-the-xbp1-arrest-peptide
#1
Theresa Kriegler, Anastasia Magoulopoulou, Rocio Amate Marchal, Tara Hessa
Secretory proteins translocate across the mammalian ER membrane co-translationally via the ribosome-sec61 translocation machinery. Signal sequences within the polypeptide, which guide this event, are diverse in their hydrophobicity, charge, length, and amino acid composition. Despite the known sequence diversity in the ER signals, it is generally assumed that they have a dominant role in determining co-translational targeting and translocation process. We have analyzed co-translational events experienced by secretory proteins carrying efficient versus inefficient signal sequencing, using an assay based on Xbp1 peptide-mediated translational arrest...
May 3, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/29719251/chaperone-mediated-sec61-channel-gating-during-er-import-of-small-precursor-proteins-overcomes-sec61-inhibitor-reinforced-energy-barrier
#2
Sarah Haßdenteufel, Nicholas Johnson, Adrienne W Paton, James C Paton, Stephen High, Richard Zimmermann
Protein transport into the mammalian endoplasmic reticulum (ER) is mediated by the heterotrimeric Sec61 channel. The signal recognition particle (SRP) and TRC systems and Sec62 have all been characterized as membrane-targeting components for small presecretory proteins, whereas Sec63 and the lumenal chaperone BiP act as auxiliary translocation components. Here, we report the transport requirements of two natural, small presecretory proteins and engineered variants using semipermeabilized human cells after the depletion of specific ER components...
May 1, 2018: Cell Reports
https://www.readbyqxmd.com/read/29701944/biosynthesis-of-t-butyl-in-apratoxin-a-functional-analysis-and-architecture-of-a-pks-loading-module
#3
Meredith A Skiba, Andrew P Sikkema, Nathan A Moss, Andrew N Lowell, Min Su, Rebecca M Sturgis, Lena Gerwick, William H Gerwick, David H Sherman, Janet L Smith
The unusual feature of a t-butyl group is found in several marine-derived natural products including apratoxin A, a Sec61 inhibitor produced by the cyanobacterium Moorea bouillonii PNG 5-198. Here we determine that the apratoxin A t-butyl group is formed as pivaloyl acyl carrier protein (ACP) by AprA, the polyketide synthase (PKS) loading module of the apratoxin A biosynthetic pathway. AprA contains an inactive "pseudo" GCN5-related N-acetyltransferase domain (ΨGNAT) flanked by two methyltransferase domains (MT1 and MT2) that differ distinctly in sequence...
April 27, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29540678/inhibition-of-sec61-dependent-translocation-by-mycolactone-uncouples-the-integrated-stress-response-from-er-stress-driving-cytotoxicity-via-translational-activation-of-atf4
#4
Joy Ogbechi, Belinda S Hall, Thomas Sbarrato, Jack Taunton, Anne E Willis, Ronald C Wek, Rachel E Simmonds
Mycolactone is the exotoxin virulence factor of Mycobacterium ulcerans that causes the neglected tropical disease Buruli ulcer. We recently showed it to be a broad spectrum inhibitor of Sec61-dependent co-translational translocation of proteins into the endoplasmic reticulum (ER). An outstanding question is the molecular pathway linking this to its known cytotoxicity. We have now used translational profiling to better understand the reprogramming that occurs in cells exposed to mycolactone. Gene ontology identified enrichment in genes involved in cellular response to stress, and apoptosis signalling among those showing enhanced translation...
March 14, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29519914/structural-basis-for-coupling-protein-transport-and-n-glycosylation-at-the-mammalian-endoplasmic-reticulum
#5
Katharina Braunger, Stefan Pfeffer, Shiteshu Shrimal, Reid Gilmore, Otto Berninghausen, Elisabet C Mandon, Thomas Becker, Friedrich Förster, Roland Beckmann
Protein synthesis, transport, and N-glycosylation are coupled at the mammalian endoplasmic reticulum by complex formation of a ribosome, the Sec61 protein-conducting channel, and oligosaccharyltransferase (OST). Here we used different cryo-electron microscopy approaches to determine structures of native and solubilized ribosome-Sec61-OST complexes. A molecular model for the catalytic OST subunit STT3A (staurosporine and temperature sensitive 3A) revealed how it is integrated into the OST and how STT3-paralog specificity for translocon-associated OST is achieved...
April 13, 2018: Science
https://www.readbyqxmd.com/read/29494533/atg5-promotes-death-signaling-in-response-to-the-cyclic-depsipeptides-coibamide-a-and-apratoxin-a
#6
Xuemei Wan, Jeffrey D Serrill, Ian R Humphreys, Michelle Tan, Kerry L McPhail, Ian G Ganley, Jane E Ishmael
Our understanding of autophagy and lysosomal function has been greatly enhanced by the discovery of natural product structures that can serve as chemical probes to reveal new patterns of signal transduction in cells. Coibamide A is a cytotoxic marine natural product that induces mTOR-independent autophagy as an adaptive stress response that precedes cell death. Autophagy-related (ATG) protein 5 (ATG5) is required for coibamide-induced autophagy but not required for coibamide-induced apoptosis. Using wild-type and autophagy-deficient mouse embryonic fibroblasts (MEFs) we demonstrate that coibamide-induced toxicity is delayed in ATG5-/- cells relative to ATG5+/+ cells...
March 1, 2018: Marine Drugs
https://www.readbyqxmd.com/read/29486236/unconventional-protein-secretion-triggered-by-nutrient-starvation
#7
REVIEW
David Cruz-Garcia, Vivek Malhotra, Amy J Curwin
It is usually assumed that eukaryotic cells secrete only proteins that contain a signal sequence for Sec61 mediated translocation into the lumen of endoplasmic reticulum (ER). Surprisingly however, many proteins, such as superoxide dismutase (SOD)1, acyl-CoA binding protein (Acb1), interleukin 1β, fibroblast growth factor 2 and the adipokine Unpaired2, to name a few, are secreted even though they lack a signal sequence. The discovery that these proteins are secreted has presented a new challenge and we describe here a common pathway by which SOD1 and Acb1 are specifically secreted upon nutrient starvation...
February 28, 2018: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/29466327/the-atomic-structure-of-a-eukaryotic-oligosaccharyltransferase-complex
#8
Lin Bai, Tong Wang, Gongpu Zhao, Amanda Kovach, Huilin Li
N-glycosylation is a ubiquitous modification of eukaryotic secretory and membrane-bound proteins; about 90% of glycoproteins are N-glycosylated. The reaction is catalysed by an eight-protein oligosaccharyltransferase (OST) complex that is embedded in the endoplasmic reticulum membrane. Our understanding of eukaryotic protein N-glycosylation has been limited owing to the lack of high-resolution structures. Here we report a 3.5 Å resolution cryo-electron microscopy structure of the Saccharomyces cerevisiae OST complex, revealing the structures of subunits Ost1-Ost5, Stt3, Wbp1 and Swp1...
March 15, 2018: Nature
https://www.readbyqxmd.com/read/29388511/impaired-transport-of-intrinsically-disordered-proteins-through-the-sec61-and-secy-translocon-implications-for-prion-diseases
#9
Sebastian Jung, Jörg Tatzelt
The prion protein (PrP) is composed of two major domains of similar size. The structured C-terminal domain contains three alpha-helical regions and a short two-stranded beta-sheet, while the N-terminal domain is intrinsically disordered. The analysis of PrP mutants with deletions in the C-terminal globular domain provided the first hint that intrinsically disordered domains are inefficiently transported into the endoplasmic reticulum through the Sec61 translocon. Interestingly, C-terminally truncated PrP mutants have been linked to inherited prion disease in humans and are characterized by inefficient ER import and the formation of neurotoxic PrP conformers...
March 29, 2018: Prion
https://www.readbyqxmd.com/read/29359838/discrimination-between-the-endoplasmic-reticulum-and-mitochondria-by-spontaneously-inserting-tail-anchored-proteins
#10
Bruna Figueiredo Costa, Patrizia Cassella, Sara F Colombo, Nica Borgese
Tail-anchored (TA) proteins insert into their target organelles by incompletely elucidated posttranslational pathways. Some TA proteins spontaneously insert into protein-free liposomes, yet target a specific organelle in vivo. Two spontaneously inserting cytochrome b5 forms, b5-ER and b5-RR, which differ only in the charge of the C-terminal region, target the endoplasmic reticulum (ER) or the mitochondrial outer membrane (MOM), respectively. To bridge the gap between the cell-free and in cellula results, we analyzed targeting in digitonin-permeabilized adherent HeLa cells...
March 2018: Traffic
https://www.readbyqxmd.com/read/29295953/the-endoplasmic-reticulum-residing-chaperone-bip-is-short-lived-and-metabolized-through-n-terminal-arginylation
#11
Sang Mi Shim, Ha Rim Choi, Ki Woon Sung, Yoon Jee Lee, Sung Tae Kim, Daeho Kim, Su Ran Mun, Joonsung Hwang, Hyunjoo Cha-Molstad, Aaron Ciechanover, Bo Yeon Kim, Yong Tae Kwon
BiP and other endoplasmic reticulum (ER)-resident proteins are thought to be metabolically stable and to function primarily in the ER lumen. We sought to assess how the abundance of these proteins dynamically fluctuates in response to various stresses and how their subpopulations are relocated to non-ER compartments such as the cytosol. We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway...
January 2, 2018: Science Signaling
https://www.readbyqxmd.com/read/29235276/-anti-tumor-target-identification-and-molecular-mechanism-study-of-total-saponins-from-albizia-julibrissin
#12
Yi Qian, Qing-Hua Han, Dan Liu, Peng-Fei Tu, Ke-Wu Zeng, Hong Liang
Dried stem bark from Albizia julibrissin(AJ) is a common traditional Chinese herb with several therapy effects including insomnia, anxiety and anti-tumor. Recently, the anti-tumor effect and mechanism studies of AJ have drawn much attention; however, there are still some troubles in chemical composition separation, which leads to the difficulties in pharmacological research of AJ. In this study, we firstly confirmed the proliferation inhibitory effect of total saponins from AJ(TSAJ)on human hepatocarcinoma(HepG2) cells, and also tested the apoptosis induction effect of TSAJ...
October 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
https://www.readbyqxmd.com/read/29168059/sec61%C3%AE-facilitates-the-maintenance-of-endoplasmic-reticulum-homeostasis-by-associating-microtubules
#13
Yimeng Zhu, Gangming Zhang, Shaoyu Lin, Juanming Shi, Hong Zhang, Junjie Hu
Sec61β, a subunit of the Sec61 translocon complex, is not essential in yeast and commonly used as a marker of endoplasmic reticulum (ER). In higher eukaryotes, such as Drosophila, deletion of Sec61β causes lethality, but its physiological role is unclear. Here, we show that Sec61β interacts directly with microtubules. Overexpression of Sec61β containing small epitope tags, but not a RFP tag, induces dramatic bundling of the ER and microtubule. A basic region in the cytosolic domain of Sec61β is critical for microtubule association...
November 22, 2017: Protein & Cell
https://www.readbyqxmd.com/read/29163222/an-update-on-sec61-channel-functions-mechanisms-and-related-diseases
#14
REVIEW
Sven Lang, Stefan Pfeffer, Po-Hsien Lee, Adolfo Cavalié, Volkhard Helms, Friedrich Förster, Richard Zimmermann
The membrane of the endoplasmic reticulum (ER) of nucleated human cells harbors the protein translocon, which facilitates membrane integration or translocation of almost every newly synthesized polypeptide targeted to organelles of the endo- and exocytotic pathway. The translocon comprises the polypeptide-conducting Sec61 channel and several additional proteins and complexes that are permanently or transiently associated with the heterotrimeric Sec61 complex. This ensemble of proteins facilitates ER targeting of precursor polypeptides, modification of precursor polypeptides in transit through the Sec61 complex, and Sec61 channel gating, i...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/29149212/mycolactone-displays-anti-inflammatory-effects-on-the-nervous-system
#15
Caroline Isaac, Annie Mauborgne, Alfonso Grimaldi, Kemy Ade, Michel Pohl, Cristina Limatola, Yves Boucher, Caroline Demangel, Laure Guenin-Macé
BACKGROUND: Mycolactone is a macrolide produced by the skin pathogen Mycobacterium ulcerans, with cytotoxic, analgesic and immunomodulatory properties. The latter were recently shown to result from mycolactone blocking the Sec61-dependent production of pro-inflammatory mediators by immune cells. Here we investigated whether mycolactone similarly affects the inflammatory responses of the nervous cell subsets involved in pain perception, transmission and maintenance. We also investigated the effects of mycolactone on the neuroinflammation that is associated with chronic pain in vivo...
November 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28918898/endoplasmic-reticulum-transport-of-glutathione-by-sec61-is-regulated-by-ero1-and-bip
#16
Alise J Ponsero, Aeid Igbaria, Maxwell A Darch, Samia Miled, Caryn E Outten, Jakob R Winther, Gael Palais, Benoit D'Autréaux, Agnès Delaunay-Moisan, Michel B Toledano
In the endoplasmic reticulum (ER), Ero1 catalyzes disulfide bond formation and promotes glutathione (GSH) oxidation to GSSG. Since GSSG cannot be reduced in the ER, maintenance of the ER glutathione redox state and levels likely depends on ER glutathione import and GSSG export. We used quantitative GSH and GSSG biosensors to monitor glutathione import into the ER of yeast cells. We found that glutathione enters the ER by facilitated diffusion through the Sec61 protein-conducting channel, while oxidized Bip (Kar2) inhibits transport...
September 21, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28860277/dc2-and-kcp2-mediate-the-interaction-between-the-oligosaccharyltransferase-and-the-er-translocon
#17
Shiteshu Shrimal, Natalia A Cherepanova, Reid Gilmore
In metazoan organisms, the STT3A isoform of the oligosaccharyltransferase is localized adjacent to the protein translocation channel to catalyze co-translational N-linked glycosylation of proteins in the endoplasmic reticulum. The mechanism responsible for the interaction between the STT3A complex and the translocation channel has not been addressed. Using genetically modified human cells that are deficient in DC2 or KCP2 proteins, we show that loss of DC2 causes a defect in co-translational N-glycosylation of proteins that mimics an STT3A-/- phenotype...
November 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28852008/retrograde-trafficking-of-%C3%AE-dystroglycan-from-the-plasma-membrane-to-the-nucleus
#18
Viridiana Gracida-Jiménez, Ricardo Mondragón-González, Griselda Vélez-Aguilera, Alejandra Vásquez-Limeta, Marco S Laredo-Cisneros, Juan de Dios Gómez-López, Luis Vaca, Sarah C Gourlay, Laura A Jacobs, Steve J Winder, Bulmaro Cisneros
β-Dystroglycan (β-DG) is a transmembrane protein with critical roles in cell adhesion, cytoskeleton remodeling and nuclear architecture. This functional diversity is attributed to the ability of β-DG to target to, and conform specific protein assemblies at the plasma membrane (PM) and nuclear envelope (NE). Although a classical NLS and importin α/β mediated nuclear import pathway has already been described for β-DG, the intracellular trafficking route by which β-DG reaches the nucleus is unknown. In this study, we demonstrated that β-DG undergoes retrograde intracellular trafficking from the PM to the nucleus via the endosome-ER network...
August 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28814507/systematic-gene-tagging-using-crispr-cas9-in-human-stem-cells-to-illuminate-cell-organization
#19
Brock Roberts, Amanda Haupt, Andrew Tucker, Tanya Grancharova, Joy Arakaki, Margaret A Fuqua, Angelique Nelson, Caroline Hookway, Susan A Ludmann, Irina A Mueller, Ruian Yang, Rick Horwitz, Susanne M Rafelski, Ruwanthi N Gunawardane
We present a CRISPR/Cas9 genome-editing strategy to systematically tag endogenous proteins with fluorescent tags in human induced pluripotent stem cells (hiPSC). To date, we have generated multiple hiPSC lines with monoallelic green fluorescent protein tags labeling 10 proteins representing major cellular structures. The tagged proteins include alpha tubulin, beta actin, desmoplakin, fibrillarin, nuclear lamin B1, nonmuscle myosin heavy chain IIB, paxillin, Sec61 beta, tight junction protein ZO1, and Tom20...
October 15, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28782656/genetics-and-mechanisms-of-hepatic-cystogenesis
#20
REVIEW
L F M van de Laarschot, J P H Drenth
Polycystic liver disease (PLD) is a heterogeneous genetic condition. PKD1 and PKD2 germline mutations are found in patients with autosomal dominant polycystic kidney disease (ADPKD). Autosomal dominant polycystic liver disease (ADPLD) is associated with germline mutations in PRKCSH, SEC63, LRP5, and recently ALG8 and SEC61. GANAB mutations are found in both patient groups. Loss of heterozygosity of PLD-genes in cyst epithelium contributes to the development of hepatic cysts. A genetic interaction network is implied in hepatic cystogenesis that connects the endoplasmic glycoprotein control mechanisms and polycystin expression and localization...
April 2018: Biochimica et Biophysica Acta
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