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Protein unfolding and translocation

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https://www.readbyqxmd.com/read/29208936/disulfide-driven-folding-for-a-conditionally-disordered-protein
#1
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
#2
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...
November 24, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29175998/structural-determinants-for-protein-unfolding-and-translocation-by-the-hsp104-protein-disaggregase
#3
Jungsoon Lee, Nuri Sung, Lythou Yeo, Changsoo Chang, Sukyeong Lee, Francis T F Tsai
The ring-forming Hsp104 ATPase cooperates with Hsp70 and Hsp40 molecular chaperones to rescue stress-damaged proteins from both amorphous and amyloid-forming aggregates. The ability to do so relies upon pore loops present in the ATP-binding domains of Hsp104 (loop-1 and loop-2 in AAA-1, and loop-3 in AAA-2), which face the protein translocating channel and couple ATP-driven changes in pore loop conformation to substrate translocation. A hallmark of loop-1 and loop-3 is an invariable and mutational sensitive aromatic amino acid (Tyr257 and Tyr662) involved in substrate binding...
November 24, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/29152155/chibby-1-a-new-component-of-%C3%AE-catenin-signaling-in-chronic-myeloid-leukemia
#4
REVIEW
Manuela Mancini, Simona Soverini, Gabriele Gugliotta, Maria Alessandra Santucci, Gianantonio Rosti, Michele Cavo, Giovanni Martinelli, Fausto Castagnetti
Chibby 1 (CBY1) is a small and evolutionarily conserved protein, which act as β-catenin antagonist. CBY1 is encoded by C22orf2 (22q13.1) Its antagonistic function on β-catenin involves the direct interaction with: The C-terminal activation domain of β-catenin, which hinders β-catenin binding with Tcf/Lef transcription factors hence repressing β-catenin transcriptional activation. 14-3-3 scaffolding proteins (σ or ξ), which drive CBY1 nuclear export into a stable tripartite complex with β-catenin. The relative proximity of C22orf2 gene encoding for CBY1 to the BCR breakpoint on chromosome 22q11, whose translocation and rearrangement with the c-ABL is the causative event of chronic myeloid leukemia (CML), suggested that gene haploinsufficiency may play a role in the disease pathogenesis and progression...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29145399/point-mutation-in-d8c-domain-of-tamm-horsfall-protein-uromodulin-in-transgenic-mice-causes-progressive-renal-damage-and-hyperuricemia
#5
Lijie Ma, Yan Liu, Nichole K Landry, Tarek M El-Achkar, John C Lieske, Xue-Ru Wu
Hereditary mutations in Tamm-Horsfall protein (THP/uromodulin) gene cause autosomal dominant kidney diseases characterized by juvenile-onset hyperuricemia, gout and progressive kidney failure, although the disease pathogenesis remains unclear. Here we show that targeted expression in transgenic mice of a mutation within the domain of 8 cysteines of THP in kidneys' thick ascending limb (TAL) caused unfolded protein response in younger (1-month old) mice and apoptosis in older (12-month old) mice. While the young mice had urine concentration defects and polyuria, such defects progressively reversed in the older mice to marked oliguria, highly concentrated urine, fibrotic kidneys and reduced creatinine clearance...
2017: PloS One
https://www.readbyqxmd.com/read/29129755/phylogenetic-analysis-predicts-structural-divergence-for-proteobacterial-clpc-proteins
#6
Justin M Miller, Hamza Chaudhary, Justin D Marsee
Regulated proteolysis is required in all organisms for the removal of misfolded or degradation-tagged protein substrates in cellular quality control pathways. The molecular machines that catalyze this process are known as ATP-dependent proteases with examples that include ClpAP and ClpCP. Clp/Hsp100 subunits form ring-structures that couple the energy of ATP binding and hydrolysis to protein unfolding and subsequent translocation of denatured protein into the compartmentalized ClpP protease for degradation...
November 9, 2017: Journal of Structural Biology
https://www.readbyqxmd.com/read/29111118/hsp90-and-thioredoxin-thioredoxin-reductase-enable-the-catalytic-activity-of-clostridial-neurotoxins-inside-nerve-terminals
#7
Marco Pirazzini, Domenico Azarnia Tehran, Giulia Zanetti, Ornella Rossetto, Cesare Montecucco
Botulinum (BoNTs) and tetanus (TeNT) neurotoxins are the most toxic substances known and form the growing family of Clostridial neurotoxins (CNT), the etiologic agents of botulism and tetanus. CNT 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 its substrates, the three SNARE proteins, are localized. L translocation is accompanied by unfolding and, once delivered on the cytosolic side of the endosome membrane, it has to be reduced and reacquire the native fold to be active...
October 27, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/29078392/exploitation-of-an-iron-transporter-for-bacterial-protein-antibiotic-import
#8
Paul White, Amar Joshi, Patrice Rassam, Nicholas G Housden, Renata Kaminska, Jonathan D Goult, Christina Redfield, Laura C McCaughey, Daniel Walker, Shabaz Mohammed, Colin Kleanthous
Unlike their descendants, mitochondria and plastids, bacteria do not have dedicated protein import systems. However, paradoxically, import of protein bacteriocins, the mechanisms of which are poorly understood, underpins competition among pathogenic and commensal bacteria alike. Here, using X-ray crystallography, isothermal titration calorimetry, confocal fluorescence microscopy, and in vivo photoactivatable cross-linking of stalled translocation intermediates, we demonstrate how the iron transporter FpvAI in the opportunistic pathogen Pseudomonas aeruginosa is hijacked to translocate the bacteriocin pyocin S2 (pyoS2) across the outer membrane (OM)...
November 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29054272/insights-on-the-hla-binding-peptidome-in-cancer
#9
Douglas F Lake
The intracellular compartments for proteolytic antigen processing in tumor cells produce peptides that are presented by MHC molecules to T cells. But first, the ubiquitin ligase system tags defective, misfolded, aged, and unstable proteins for degradation through the proteasome. Ubiqitinated proteins are unfolded and fed into the barrel-shaped core of the proteasome where a collection of multiple different proteases cleave proteins into oligopeptides. After exiting the proteasome, these oligopeptides are either completely degraded into amino acids or trimmed at the N- and C-termini so that they bind to transporter associated with antigen processing (TAP)...
2017: Enzymes
https://www.readbyqxmd.com/read/29030433/dysregulation-of-the-mitochondrial-unfolded-protein-response-induces-non-apoptotic-dopaminergic-neurodegeneration-in-c-elegans-models-of-parkinson-s-disease
#10
Bryan A Martinez, Daniel A Petersen, Anthony L Gaeta, Samuel P Stanley, Guy A Caldwell, Kim A Caldwell
Due to environmental insult or innate genetic deficiency, protein folding environments of the mitochondrial matrix are prone to dysregulation, prompting the activation of a specific organellar stress-response mechanism, the mitochondrial unfolded protein response (UPR(MT)). In Caenorhabditis elegans, mitochondrial damage leads to nuclear translocation of the ATFS-1 transcription factor to activate the UPR(MT) After short-term acute stress has been mitigated, the UPR(MT) is eventually suppressed to restore homeostasis to C...
November 15, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28988953/meddling-with-fate-the-proteasomal-deubiquitinating-enzymes
#11
REVIEW
Stefanie A H de Poot, Geng Tian, Daniel Finley
Three deubiquitinating enzymes-Rpn11, Usp14, and Uch37-are associated with the proteasome regulatory particle. These enzymes allow proteasomes to remove ubiquitin from substrates before they are translocated into the core particle to be degraded. Although the translocation channel is too narrow for folded proteins, the force of translocation unfolds them mechanically. As translocation proceeds, ubiquitin chains bound to substrate are drawn to the channel's entry port, where they can impede further translocation...
November 10, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28980803/analysis-of-pore-formation-and-protein-translocation-using-large-biological-nanopores
#12
Hirokazu Watanabe, Alberto Gubbiotti, Mauro Chinappi, Natsumi Takai, Koji Tanaka, Kouhei Tsumoto, Ryuji Kawano
This paper describes the analysis of pore formation and detection of a single protein molecule using a large nanopore among five different pore-forming proteins. We demonstrate that the identification of appropriate pores for nanopore sensing can be achieved by classifying the channel current signals and performing noise analysis. Through these analyses, we selected a perforin nanopore from the membrane attack complex/perforin superfamily and attempted to use it to detect the granzyme B protein, a serine protease...
November 7, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28978049/ros-independent-nrf2-activation-in-prostate-cancer
#13
Ilaria Bellezza, Paolo Scarpelli, Salvatore V Pizzo, Silvia Grottelli, Egidia Costanzi, Alba Minelli
In prostate cancer, oxidative stress and the subsequent Nrf2 activation promote the survival of cancer cells and acquired chemoresistance. Nrf2 links prostate cancer to endoplasmic reticulum stress, an event that triggers the unfolded protein response, aiming to restore cellular homeostasis as well as an adaptive survival mechanism. Glucose-regulated protein of 78 kD /immunoglobulin heavy chain binding protein (GRP78/BiP) is a key molecular chaperone in the endoplasmic reticulum that, when expressed at the cell surface, acts as a receptor for several signaling pathways enhancing antiapoptotic and proliferative signals...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28920507/navigating-the-structure-function-evolutionary-relationship-of-csaa-chaperone-in-archaea
#14
Archana Sharma, Shikha Rani, Manisha Goel
CsaA is a protein involved in the post-translational translocation of proteins across the cytoplasmic membrane. It is considered to be a functional homolog of SecB which participates in the Sec-dependent translocation pathway in an analogous manner. CsaA has also been reported to act as a molecular chaperone, preventing aggregation of unfolded proteins. It is essentially a prokaryotic protein which is absent in eukaryotes, but found extensively in bacteria and earlier thought to be widely present in archaea...
September 18, 2017: Critical Reviews in Microbiology
https://www.readbyqxmd.com/read/28904818/nf-%C3%AE%C2%BAb-pathway-link-with-er-stress-induced-autophagy-and-apoptosis-in-cervical-tumor-cells
#15
Xiaolan Zhu, Li Huang, Jie Gong, Chun Shi, Zhiming Wang, Bingkun Ye, Aiguo Xuan, Xiaosong He, Dahong Long, Xiao Zhu, Ningfang Ma, Shuilong Leng
Targeting endoplasmic reticulum (ER) stress is being investigated for its anticancer effect in various cancers, including cervical cancer. However, the molecular pathways whereby ER stress mediates cell death remain to be fully elucidated. In this study, we confirmed that ER stress triggered by compounds such as brefeldin A (BFA), tunicamycin (TM), and thapsigargin (TG) leads to the induction of the unfolded protein response (UPR) in cervical cancer cell lines, which is characterized by elevated levels of inositol-requiring kinase 1α, glucose-regulated protein-78, and C/EBP homologous protein, and swelling of the ER observed by transmission electron microscope (TEM)...
2017: Cell Death Discovery
https://www.readbyqxmd.com/read/28878026/the-p97-inhibitor-cb-5083-is-a-unique-disrupter-of-protein-homeostasis-in-models-of-multiple-myeloma
#16
Ronan Le Moigne, Blake T Aftab, Stevan Djakovic, Eugen Dhimolea, Eduardo Valle, Megan Murnane, Emily M King, Ferdie Soriano, Mary-Kamala Menon, Zhi Yong Wu, Stephen T Wong, Grace J Lee, Bing Yao, Arun P Wiita, Christine Lam, Julie Rice, Jinhai Wang, Marta Chesi, P Leif Bergsagel, Marianne Kraus, Christoph Driessen, Szerenke Kiss von Soly, F Michael Yakes, David Wustrow, Laura Shawver, Han-Jie Zhou, Thomas G Martin, Jeffrey L Wolf, Constantine S Mitsiades, Daniel J Anderson, Mark Rolfe
Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis...
November 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28844860/an-aaa-motor-driven-mechanical-switch-in-rpn11-controls-deubiquitination-at-the-26s-proteasome
#17
Evan J Worden, Ken C Dong, Andreas Martin
Poly-ubiquitin chains direct protein substrates to the 26S proteasome, where they are removed by the deubiquitinase Rpn11 during ATP-dependent substrate degradation. Rapid deubiquitination is required for efficient degradation but must be restricted to committed substrates that are engaged with the ATPase motor to prevent premature ubiquitin chain removal and substrate escape. Here we reveal the ubiquitin-bound structure of Rpn11 from S. cerevisiae and the mechanisms for mechanochemical coupling of substrate degradation and deubiquitination...
September 7, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28815021/toward-an-understanding-of-the-cdc48-p97-atpase
#18
REVIEW
Nicholas Bodnar, Tom Rapoport
A conserved AAA+ ATPase, called Cdc48 in yeast and p97 or VCP in metazoans, plays an essential role in many cellular processes by segregating polyubiquitinated proteins from complexes or membranes. For example, in endoplasmic reticulum (ER)-associated protein degradation (ERAD), Cdc48/p97 pulls polyubiquitinated, misfolded proteins out of the ER and transfers them to the proteasome. Cdc48/p97 consists of an N-terminal domain and two ATPase domains (D1 and D2). Six Cdc48 monomers form a double-ring structure surrounding a central pore...
2017: F1000Research
https://www.readbyqxmd.com/read/28811582/a-new-class-of-hybrid-secretion-system-is-employed-in-pseudomonas-amyloid-biogenesis
#19
Sarah L Rouse, William J Hawthorne, Jamie-Lee Berry, Dror S Chorev, Sandra A Ionescu, Sebastian Lambert, Fisentzos Stylianou, Wiebke Ewert, Uma Mackie, R Marc L Morgan, Daniel Otzen, Florian-Alexander Herbst, Per H Nielsen, Morten Dueholm, Hagan Bayley, Carol V Robinson, Stephen Hare, Stephen Matthews
Gram-negative bacteria possess specialised biogenesis machineries that facilitate the export of amyloid subunits for construction of a biofilm matrix. The secretion of bacterial functional amyloid requires a bespoke outer-membrane protein channel through which unfolded amyloid substrates are translocated. Here, we combine X-ray crystallography, native mass spectrometry, single-channel electrical recording, molecular simulations and circular dichroism measurements to provide high-resolution structural insight into the functional amyloid transporter from Pseudomonas, FapF...
August 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28782633/plasma-cell-deficiency-in-human-subjects-with-heterozygous-mutations-in-sec61-translocon-alpha-1-subunit-sec61a1
#20
Desirée Schubert, Marie-Christine Klein, Sarah Hassdenteufel, Andrés Caballero-Oteyza, Linlin Yang, Michele Proietti, Alla Bulashevska, Janine Kemming, Johannes Kühn, Sandra Winzer, Stephan Rusch, Manfred Fliegauf, Alejandro A Schäffer, Stefan Pfeffer, Roger Geiger, Adolfo Cavalié, Hongzhi Cao, Fang Yang, Yong Li, Marta Rizzi, Hermann Eibel, Robin Kobbe, Amy L Marks, Brian P Peppers, Robert W Hostoffer, Jennifer M Puck, Richard Zimmermann, Bodo Grimbacher
BACKGROUND: Primary antibody deficiencies (PADs) are the most frequent primary immunodeficiencies in human subjects. The genetic causes of PADs are largely unknown. Sec61 translocon alpha 1 subunit (SEC61A1) is the major subunit of the Sec61 complex, which is the main polypeptide-conducting channel in the endoplasmic reticulum membrane. SEC61A1 is a target gene of spliced X-box binding protein 1 and strongly induced during plasma cell (PC) differentiation. OBJECTIVE: We identified a novel genetic defect and studied its pathologic mechanism in 11 patients from 2 unrelated families with PADs...
August 4, 2017: Journal of Allergy and Clinical Immunology
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