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Protein unfolding and translocation

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https://www.readbyqxmd.com/read/28069863/ubiquitin-recognition-by-the-proteasome
#1
REVIEW
Yasushi Saeki
The 26S proteasome is a 2.5-MDa complex responsible for the selective, ATP-dependent degradation of ubiquitylated proteins in eukaryotic cells. Substrates in hundreds cellular pathways are timely ubiquitylated and converged to the proteasome by direct recognition or by multiple shuttle factors. Engagement of substrate protein triggers conformational changes of the proteasome, which drive substrate unfolding, deubiquitylation and translocation of substrates to proteolytic sites. Recent studies have challenged the previous paradigm that Lys48-linked tetraubiquitin is a minimal degradation signal: in addition, monoubiquitylation or multiple short ubiquitylations can serve as the targeting signal for proteasomal degradation...
January 8, 2017: Journal of Biochemistry
https://www.readbyqxmd.com/read/28067475/the-chaperonin-tric-forms-an-oligomeric-complex-in-the-malaria-parasite-cytosol
#2
Natalie J Spillman, Josh R Beck, Suresh M Ganesan, Jacquin C Niles, Daniel E Goldberg
The malaria parasite exports numerous proteins into its host red blood cell (RBC). The trafficking of these exported effectors is complex. Proteins are first routed through the secretory system, into the parasitophorous vacuole (PV), a membranous compartment enclosing the parasite. Proteins are then translocated across the PV membrane in a process requiring ATP and unfolding. Once in the RBC compartment the exported proteins are then refolded and further trafficked to their final localizations. Chaperones are important in the unfolding and refolding processes...
January 9, 2017: Cellular Microbiology
https://www.readbyqxmd.com/read/28032645/arabidopsis-b-cell-lymphoma2-bcl-2-associated-athanogene-7-bag7-mediated-heat-tolerance-requires-translocation-sumoylation-and-binding-to-wrky29
#3
Yurong Li, Brett Williams, Martin Dickman
To cope with stress and increased accumulation of misfolded proteins, plants and animals use a survival pathway known as the unfolded protein response (UPR) that signals between the endoplasmic reticulum (ER) and the nucleus to maintain cell homeostasis via proper folding of proteins. B-cell lymphoma2 (Bcl-2)-associated athanogene (BAG) proteins are an evolutionarily conserved family of co-chaperones that are linked to disease states in mammals and responses to environmental stimuli (biotic and abiotic) in plants...
December 29, 2016: New Phytologist
https://www.readbyqxmd.com/read/28010734/proteins-adopt-functionally-active-conformations-after-type-iii-secretion
#4
Kevin James Metcalf, James Lea Bevington, Sandy Lisette Rosales, Lisa Ann Burdette, Elias Valdivia, Danielle Tullman-Ercek
BACKGROUND: Bacterial production of natively folded heterologous proteins by secretion to the extracellular space can improve protein production by simplifying purification and enabling continuous processing. In a typical bacterial protein production process, the protein of interest accumulates in the cytoplasm of the cell, requiring cellular lysis and extensive purification to separate the desired protein from other cellular constituents. The type III secretion system of Gram-negative bacteria is used to secrete proteins from the cytosol to the extracellular space in one step, but proteins must unfold during translocation, necessitating the folding of secreted proteins in the extracellular space for an efficient production process...
December 23, 2016: Microbial Cell Factories
https://www.readbyqxmd.com/read/27981232/strain-dependent-recognition-of-a-unique-degradation-motif-by-clpxp-in-streptococcus-mutans
#5
Biswanath Jana, Liang Tao, Indranil Biswas
Streptococcus mutans, a dental pathogen, has a remarkable ability to cope with environmental stresses. Under stress conditions, cytoplasmic proteases play a major role in controlling the stability of regulatory proteins and preventing accumulation of damaged and misfolded proteins. ClpXP, a well-conserved cytoplasmic proteolytic system, is crucial in maintaining cellular homeostasis in bacteria. ClpX is primarily responsible for recognition of substrates and subsequent translocation of unfolded substrates into the ClpP proteolytic compartment for degradation...
November 2016: MSphere
https://www.readbyqxmd.com/read/27960258/mechanism-of-the-spontaneous-and-directional-membrane-insertion-of-a-2-transmembrane-ion-channel
#6
Steffen Altrichter, Maximilian Haase, Belinda Loh, Andreas Kuhn, Sebastian Leptihn
Protein insertion into membranes is a process occurring in every cell and every cellular compartment. Yet, many thermodynamic aspects of this fundamental biophysical process are not well understood. We investigated physicochemical parameters that influence protein insertion using the model protein KcsA, a 2-transmembrane ion channel. To understand what drives insertion and to identify individual steps of protein integration into a highly apolar environment, we investigated the contribution of electrostatic interactions and lipid composition on protein insertion on a single molecule level...
December 21, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27864322/escherichia-coli-proteome-microarrays-identified-the-substrates-of-clpyq-protease
#7
Chih-Hsuan Tsai, Yu-Hsuan Ho, Tzu-Cheng Sung, Whei-Fen Wu, Chien-Sheng Chen
Proteolysis is a vital mechanism to regulate the cellular proteome in all kingdoms of life, and ATP-dependent proteases play a crucial role within this process. In Escherichia coli, ClpYQ is one of the primary ATP-dependent proteases. In addition to function with removals of abnormal peptides in the cells, ClpYQ degrades regulatory proteins if necessary and thus let cells adjust to various environmental conditions. In E. coli, SulA, RcsA, RpoH and TraJ as well as RNase R, have been identified as natural protein substrates of ClpYQ...
January 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/27844434/mechanically-watching-the-clpxp-proteolytic-machinery
#8
Juan Carlos Cordova, Adrian O Olivares, Matthew J Lang
Energy-dependent protein degradation is studied through the dual bead ClpXP motility assay. Processing of folded proteins involves recognition, unfolding, translocation, and degradation stages. A dual optical trap, in a passive force-clamp geometry, exhibits bead-to-bead displacements that directly follow subprocesses underlying protein degradation. Discrete nanometer-scale displacements of the bead position reveal steps, dwells and pauses during the unfolding and translocation substeps. With a few structural modifications to the protease machinery and an engineered substrate, the assay represents a "chassis" for the measurement of a wide range of substrates and related machinery...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27806276/the-ph-dependent-trigger-in-diphtheria-toxin-t-domain-comes-with-a-safety-latch
#9
Mykola V Rodnin, Jing Li, Michael L Gross, Alexey S Ladokhin
Protein-side-chain protonation, coupled to conformational rearrangements, is one way of regulating physiological function caused by changes in protein environment. Specifically, protonation of histidine residues has been implicated in pH-dependent conformational switching in several systems, including the diphtheria toxin translocation (T) domain, which is responsible for the toxin's cellular entry via the endosomal pathway. Our previous studies a) identified protonation of H257 as a major component of the T domain's conformational switch and b) suggested the possibility of a neighboring H223 acting as a modulator, affecting the protonation of H257 and preventing premature conformational changes outside the endosome...
November 1, 2016: Biophysical Journal
https://www.readbyqxmd.com/read/27791164/structural-basis-for-dynamic-regulation-of-the-human-26s-proteasome
#10
Shuobing Chen, Jiayi Wu, Ying Lu, Yong-Bei Ma, Byung-Hoon Lee, Zhou Yu, Qi Ouyang, Daniel J Finley, Marc W Kirschner, Youdong Mao
The proteasome is the major engine of protein degradation in all eukaryotic cells. At the heart of this machine is a heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitylated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides. Using cryoelectron microscopy, we determined a near-atomic-resolution structure of the 2.5-MDa human proteasome in its ground state, as well as subnanometer-resolution structures of the holoenzyme in three alternative conformational states...
November 15, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27749824/translocon-component-sec62-acts-in-endoplasmic-reticulum-turnover-during-stress-recovery
#11
Fiorenza Fumagalli, Julia Noack, Timothy J Bergmann, Eduardo Cebollero, Giorgia Brambilla Pisoni, Elisa Fasana, Ilaria Fregno, Carmela Galli, Marisa Loi, Tatiana Soldà, Rocco D'Antuono, Andrea Raimondi, Martin Jung, Armin Melnyk, Stefan Schorr, Anne Schreiber, Luca Simonelli, Luca Varani, Caroline Wilson-Zbinden, Oliver Zerbe, Kay Hofmann, Matthias Peter, Manfredo Quadroni, Richard Zimmermann, Maurizio Molinari
The endoplasmic reticulum (ER) is a site of protein biogenesis in eukaryotic cells. Perturbing ER homeostasis activates stress programs collectively called the unfolded protein response (UPR). The UPR enhances production of ER-resident chaperones and enzymes to reduce the burden of misfolded proteins. On resolution of ER stress, ill-defined, selective autophagic programs remove excess ER components. Here we identify Sec62, a constituent of the translocon complex regulating protein import in the mammalian ER, as an ER-resident autophagy receptor...
November 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27670897/structure-of-anthrax-lethal-toxin-prepore-complex-suggests-a-pathway-for-efficient-cell-entry
#12
Lucien Fabre, Eugenio Santelli, Driss Mountassif, Annemarie Donoghue, Aviroop Biswas, Rikard Blunck, Dorit Hanein, Niels Volkmann, Robert Liddington, Isabelle Rouiller
Anthrax toxin comprises three soluble proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). PA must be cleaved by host proteases before it oligomerizes and forms a prepore, to which LF and EF bind. After endocytosis of this tripartite complex, the prepore transforms into a narrow transmembrane pore that delivers unfolded LF and EF into the host cytosol. Here, we find that translocation of multiple 90-kD LF molecules is rapid and efficient. To probe the molecular basis of this translocation, we calculated a three-dimensional map of the fully loaded (PA63)7-(LF)3 prepore complex by cryo-electron microscopy (cryo-EM)...
October 2016: Journal of General Physiology
https://www.readbyqxmd.com/read/27669037/substrate-translocating-loops-regulate-mechanochemical-coupling-and-power-production-in-aaa-protease-clpxp
#13
Piere Rodriguez-Aliaga, Luis Ramirez, Frank Kim, Carlos Bustamante, Andreas Martin
ATP-dependent proteases of the AAA+ family, including Escherichia coli ClpXP and the eukaryotic proteasome, contribute to maintenance of cellular proteostasis. ClpXP unfolds and translocates substrates into an internal degradation chamber, using cycles of alternating dwell and burst phases. The ClpX motor performs chemical transformations during the dwell and translocates the substrate in increments of 1-4 nm during the burst, but the processes occurring during these phases remain unknown. Here we characterized the complete mechanochemical cycle of ClpXP, showing that ADP release and ATP binding occur nonsequentially during the dwell, whereas ATP hydrolysis and phosphate release occur during the burst...
November 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27667691/a-structurally-dynamic-region-of-the-hslu-intermediate-domain-controls-protein-degradation-and-atp-hydrolysis
#14
Vladimir Baytshtok, Xue Fei, Robert A Grant, Tania A Baker, Robert T Sauer
The I domain of HslU sits above the AAA+ ring and forms a funnel-like entry to the axial pore, where protein substrates are engaged, unfolded, and translocated into HslV for degradation. The L199Q I-domain substitution, which was originally reported as a loss-of-function mutation, resides in a segment that appears to adopt multiple conformations as electron density is not observed in HslU and HslUV crystal structures. The L199Q sequence change does not alter the structure of the AAA+ ring or its interactions with HslV but increases I-domain susceptibility to limited endoproteolysis...
October 4, 2016: Structure
https://www.readbyqxmd.com/read/27645929/astragalus-polysaccharide-modulates-er-stress-response-in-an-ova-lps-induced-murine-model-of-severe-asthma
#15
Yuan Lu, Qiong-Qiong Xing, Jian-Ya Xu, Dou Ding, Xia Zhao
Endoplasmic reticulum (ER) stress has been recently revealed to play a pivotal role in the pathogenesis of severe asthma. Astragalus polysaccharide (APS), a major bioactive component from Astragalus membranaceus, exerts immunomodulatory and anti-inflammatory effects and has been shown to suppress ER stress in chronic diseases such as type-2 diabetes. However, the pharmaceutical application of APS in the treatment of severe asthma is unknown. The results obtained here indicate that APS significantly attenuates eosinophils and neutrophil-dominant airway inflammation by reducing the mRNA levels of Cxcl5, Il8, and chemokine (C-C motif) ligand 20 (Ccl20) and the protein levels of IL13RA and IL17RA...
December 2016: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/27573243/bacterial-n-glycosylation-efficiency-is-dependent-on-the-structural-context-of-target-sequons
#16
Julie Michelle Silverman, Barbara Imperiali
Site selectivity of protein N-linked glycosylation is dependent on many factors, including accessibility of the modification site, amino acid composition of the glycosylation consensus sequence, and cellular localization of target proteins. Previous studies have shown that the bacterial oligosaccharyltransferase, PglB, of Campylobacter jejuni favors acceptor proteins with consensus sequences ((D/E)X1NX2(S/T), where X1,2 ≠ proline) in flexible, solvent-exposed motifs; however, several native glycoproteins are known to harbor consensus sequences within structured regions of the acceptor protein, suggesting that unfolding or partial unfolding is required for efficient N-linked glycosylation in the native environment...
October 14, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27536862/the-colicin-e1-tolc-binding-conformer-pillar-or-pore-function-of-tolc-in-colicin-import
#17
Stanislav D Zakharov, Xin S Wang, William A Cramer
The mechanism by which the drug export protein TolC is utilized for import of the cytotoxin colicin E1 across the outer membrane and periplasmic space is addressed. Studies of the initial binding of colicin E1 with TolC, occlusion of membrane-incorporated TolC ion channels, and the structure underlying the colicin-TolC complex were based on the interactions with TolC of individual colicin translocation domain (T-domain) peptides from a set of 19 that span different segments of the T-domain. These studies led to identification of a short 20-residue segment 101-120, a "TolC box", located near the center of the colicin T-domain, which is necessary for binding of colicin to TolC...
September 13, 2016: Biochemistry
https://www.readbyqxmd.com/read/27515399/a-novel-in-vitro-cypd-mediated-p53-aggregation-assay-suggests-a-model-for-mitochondrial-permeability-transition-by-chaperone-systems
#18
Ivan Lebedev, Alice Nemajerova, Zachariah H Foda, Maja Kornaj, Michael Tong, Ute M Moll, Markus A Seeliger
Tissue necrosis as a consequence of ischemia-reperfusion injury and oxidative damage is a leading cause of permanent disability and death worldwide. The complete mechanism by which cells undergo necrosis upon oxidative stress is not understood. In response to an oxidative insult, wild-type p53 has been implicated as a central regulatory component of the mitochondrial permeability transition (mPT), triggering necrosis. This process is associated with cellular stabilization and translocation of p53 into the mitochondrial matrix...
October 9, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27425826/unfolding-knots-by-proteasome-like-systems-simulations-of-the-behaviour-of-folded-and-neurotoxic-proteins
#19
Michał Wojciechowski, Àngel Gómez-Sicilia, Mariano Carrión-Vázquez, Marek Cieplak
Knots in proteins have been proposed to resist proteasomal degradation. Ample evidence associates proteasomal degradation with neurodegeneration. One interesting possibility is that indeed knotted conformers stall this machinery leading to toxicity. However, although the proteasome is known to unfold mechanically its substrates, at present there are no experimental methods to emulate this particular traction geometry. Here, we consider several dynamical models of the proteasome in which the complex is represented by an effective potential with an added pulling force...
August 16, 2016: Molecular BioSystems
https://www.readbyqxmd.com/read/27404998/hsp90-is-involved-in-the-entry-of-clostridial-neurotoxins-into-the-cytosol-of-nerve-terminals
#20
Domenico Azarnia Tehran, Marco Pirazzini, Oneda Leka, Andrea Mattarei, Florigio Lista, Thomas Binz, Ornella Rossetto, Cesare Montecucco
Botulinum and tetanus neurotoxins are the most toxic substances known and form the growing family of clostridial neurotoxins. They are composed of a metalloprotease light chain (L), linked via a disulfide bond to a heavy chain (H). H mediates the binding to nerve terminals and the membrane translocation of L into the cytosol where their substrates, the three SNARE proteins, are localised. L translocation is accompanied by unfolding, and it has to be reduced and reacquire the native fold to exert its neurotoxicity...
July 12, 2016: Cellular Microbiology
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