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https://www.readbyqxmd.com/read/30118682/an-mtb-human-protein-protein-interaction-map-identifies-a-switch-between-host-antiviral-and-antibacterial-responses
#1
Bennett H Penn, Zoe Netter, Jeffrey R Johnson, John Von Dollen, Gwendolyn M Jang, Tasha Johnson, Yamini M Ohol, Cyrus Maher, Samantha L Bell, Kristina Geiger, Guillaume Golovkine, Xiaotang Du, Alex Choi, Trevor Parry, Bhopal C Mohapatra, Matthew D Storck, Hamid Band, Chen Chen, Stefanie Jäger, Michael Shales, Dan A Portnoy, Ryan Hernandez, Laurent Coscoy, Jeffery S Cox, Nevan J Krogan
Although macrophages are armed with potent antibacterial functions, Mycobacterium tuberculosis (Mtb) replicates inside these innate immune cells. Determinants of macrophage intrinsic bacterial control, and the Mtb strategies to overcome them, are poorly understood. To further study these processes, we used an affinity tag purification mass spectrometry (AP-MS) approach to identify 187 Mtb-human protein-protein interactions (PPIs) involving 34 secreted Mtb proteins. This interaction map revealed two factors involved in Mtb pathogenesis-the secreted Mtb protein, LpqN, and its binding partner, the human ubiquitin ligase CBL...
August 16, 2018: Molecular Cell
https://www.readbyqxmd.com/read/30118589/sequencing-grade-tandem-mass-spectrometry-for-top-down-proteomics-using-hybrid-electron-capture-dissociation-methods-in-a-benchtop-orbitrap-mass-spectrometer
#2
Jared B Shaw, Neha Malhan, Yury V Vasil'ev, Nathan I Lopez, Alexander A Makarov, Joseph S Beckman, Valery G Voinov
Compared to traditional collision induced dissociation methods, electron capture dissociation (ECD) provides more comprehensive characterization of large peptides and proteins and preserves labile post-translational modifications. However, ECD experiments are generally restricted to the high magnetic fields of FTICR-MS that enable simultaneous trapping of large polycations and electrons. Here, we demonstrate the use of an electromagnetostatic ECD cell to perform ECD and hybrid ECD methods utilizing 193 nm photons (ECuvPD) or collisional activation (EChcD) in a benchtop quadrupole-Orbitrap mass spectrometer...
August 17, 2018: Analytical Chemistry
https://www.readbyqxmd.com/read/30118587/homo-protacs-for-the-chemical-knockdown-of-cereblon
#3
Christian Steinebach, Stefanie Lindner, Namrata D Udeshi, Deepak C Mani, Hannes Kehm, Simon Köpff, Steven A Carr, Michael Gütschow, Jan Kronke
The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide, all approved for the treatment of multiple myeloma, induce targeted ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3) via the cereblon (CRBN) E3 ubiquitin ligase. IMiD-based proteolysis targeting chimeras (PROTACs) can efficiently recruit CRBN to a protein of interest leading to its ubiquitination and proteasomal degradation. By linking two pomalidomide molecules, we designed homobifunctional, so-called Homo-PROTACs and investigated their ability to induce self-directed ubiquitination and degradation...
August 17, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30117511/native-chemical-ligation-at-methionine-bioisostere-norleucine-allows-for-n-terminal-chemical-protein-ligation
#4
Bo-Tao Xin, Bianca D M van Tol, Huib Ovaa, Paul P Geurink
The development of γ-thionorleucine (ThioNle) as a handle for native chemical ligation-desulfurization is reported here. ThioNle is a new addition to the expanding thiolated amino acid toolbox and serves as a methionine substitute in NCL with the advantage that it lacks the undesirable oxidation-prone thioether moiety. Its usefulness for N-terminal ubiquitination is demonstrated by efficient preparation of fully synthetic linear diubiquitin with preserved protein folding compared to the expressed material...
August 17, 2018: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/30112000/inhibition-of-mdm2-via-nutlin-3a-a-potential-therapeutic-approach-for-pleural-mesotheliomas-with-mdm2-induced-inactivation-of-wild-type-p53
#5
Robert F H Walter, Robert Werner, Michael Wessolly, Elena Mairinger, Sabrina Borchert, Jan Schmeller, Jens Kollmeier, Thomas Mairinger, Thomas Hager, Agnes Bankfalvi, Daniel C Christoph, Wilfried E E Eberhardt, Till Plönes, Clemens Aigner, Kurt W Schmid, Jeremias Wohlschlaeger, Fabian D Mairinger
Previously, our group demonstrated that nuclear expression of E3 ubiquitin ligase (MDM2) in malignant pleural mesothelioma (MPM) is significantly associated with decreased overall survival. A possible explanation may be that overexpression of MDM2 leads to a proteasomal degradation of TP53 that eventually results in a loss of TP53-induced apoptosis and senescence. It is well known from other tumor entities that restoration of TP53 activity, e.g., by MDM2 inhibition, results in an instant TP53-induced stress and/or DNA damage response of cancer cells...
2018: Journal of Oncology
https://www.readbyqxmd.com/read/30109411/untying-the-knot-protein-quality-control-in-inherited-cardiomyopathies
#6
REVIEW
Larissa M Dorsch, Maike Schuldt, Dora Knežević, Marit Wiersma, Diederik W D Kuster, Jolanda van der Velden, Bianca J J M Brundel
Mutations in genes encoding sarcomeric proteins are the most important causes of inherited cardiomyopathies, which are a major cause of mortality and morbidity worldwide. Although genetic screening procedures for early disease detection have been improved significantly, treatment to prevent or delay mutation-induced cardiac disease onset is lacking. Recent findings indicate that loss of protein quality control (PQC) is a central factor in the disease pathology leading to derailment of cellular protein homeostasis...
August 14, 2018: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/30107089/ubxn2a-enhances-chip-mediated-proteasomal-degradation-of-oncoprotein-mortalin-2-in-cancer-cells
#7
Sanam Sane, Andre Hafner, Rekha Srinivasan, Daniall Masood, John L Slunecka, Collin J Noldner, Alex D Hanson, Taylor Kruisselbrink, Xuejun Wang, Yiyang Wang, Jun Yin, Khosrow Rezvani
Overexpression of oncoproteins is a major cause of treatment failure using current chemotherapeutic drugs. Drug-induced degradation of oncoproteins is feasible and can improve clinical outcomes in diverse types of cancers. Mortalin-2 (mot-2) is a dominant oncoprotein in several tumors, including colorectal cancer (CRC). In addition to inactivating the p53 tumor suppressor protein, mot-2 enhances tumor cell invasion and migration. Thus, mot-2 is considered a potential therapeutic target in several cancer types...
August 14, 2018: Molecular Oncology
https://www.readbyqxmd.com/read/30098445/analysis-and-identification-of-tyrosine-phosphorylated-proteins-in-hemocytes-of-litopenaeus-vannamei-infected-with-wssv
#8
Xiaoqian Tang, Xiaoai Li, Fude Zhai, Jing Xing, Xiuzhen Sheng, Wenbin Zhan
Previous studies have demonstrated that protein tyrosine phosphorylation plays an important role in WSSV infection. In the present work, in order to further elucidate the potential role of protein tyrosine phosphorylation in white spot syndrome virus (WSSV) infection. The expression variation of tyrosine phosphorylated proteins in hemocytes of shrimp (Litopenaeus vannamei) after WSSV infection were examined by flow cytometric immunofluorescence assay (FCIFA) and enzyme linked immunosorbent assay (ELISA), and results showed that the level of protein tyrosine phosphorylation in hemocytes fluctuated significantly after WSSV infection and exhibited two peaks at 6 and 24 h post infection (hpi)...
August 8, 2018: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/30091673/er-associated-degradation-and-disposal-of-misfolded-gpi-anchored-proteins-in-trypanosoma-brucei
#9
Calvin Tiengwe, Carolina M Koeller, James D Bangs
Misfolded secretory proteins are retained by ER quality control (ERQC) and degraded in the proteasome by ER associated degradation (ERAD). However, in yeast and mammals misfolded glycosylphosphatidylinositol (GPI)-anchored proteins are preferentially degraded in the vacuole/lysosome. We investigate this process in the divergent eukaryotic pathogen Trypanosoma brucei using a misfolded GPI-anchored subunit (HA:E6) of the trypanosome transferrin receptor. HA:E6 is N-glycosylated and GPI-anchored, and accumulates in the ER as aggregates...
August 9, 2018: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/30066433/variation-at-the-trim11-locus-modifies-progressive-supranuclear-palsy-phenotype
#10
E Jabbari, J Woodside, Mmx Tan, M Shoai, A Pittman, R Ferrari, K Y Mok, D Zhang, R H Reynolds, R de Silva, M J Grimm, G Respondek, U Müller, S Al-Sarraj, S M Gentleman, A J Lees, T T Warner, J Hardy, T Revesz, G U Höglinger, J L Holton, M Ryten, H R Morris
OBJECTIVE: The basis for clinical variation related to underlying Progressive Supranuclear Palsy (PSP) pathology is unknown. We performed a genome wide association study (GWAS) to identify genetic determinants of PSP phenotype. METHODS: Two independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardson's syndrome (RS) and non-RS groups. We carried out separate logistic regression GWAS to compare RS and non-RS groups and then combined datasets to carry out a whole cohort analysis (RS=367, non-RS=130)...
July 31, 2018: Annals of Neurology
https://www.readbyqxmd.com/read/30064974/crbn-i391v-is-sufficient-to-confer-in-vivo-sensitivity-to-thalidomide-and-its-derivatives-in-mice
#11
Emma C Fink, Marie McConkey, Dylan N Adams, Saurav D Haldar, James A Kennedy, Andrew A Guirguis, Namrata D Udeshi, D R Mani, Michelle Chen, Brian Liddicoat, Tanya Svinkina, Andrew T Nguyen, Steven A Carr, Benjamin L Ebert
Thalidomide and its derivatives, lenalidomide and pomalidomide, are clinically effective treatments for multiple myeloma and myelodysplastic syndrome with del(5q). These molecules lack activity in murine models, limiting investigation of their therapeutic activity or toxicity in vivo Here, we report the development of a mouse model that is sensitive to thalidomide derivatives due to a single amino acid change in the direct target of thalidomide derivatives, Crbn. In human cells, thalidomide and its analogs bind CRBN and recruit protein targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and subsequent degradation by the proteasome...
July 31, 2018: Blood
https://www.readbyqxmd.com/read/30062698/vaccinia-related-kinase-2-modulates-role-of-dysbindin-by-regulating-protein-stability
#12
Young-Hun Jeong, Jung-Hyun Choi, Dohyun Lee, Sangjune Kim, Kyong-Tai Kim
Vaccinia-related kinase 2 (VRK2) is a serine/threonine kinase that belongs to the casein kinase 1 family. VRK2 has long been known for its relationship with to neurodegenerative disorders such as schizophrenia. However, the role of VRK2 and the substrates associated with it are unknown. Dysbindin is known as one of the strong risk factors for schizophrenia. The expression of dysbindin is indeed significantly reduced in schizophrenia patients. Moreover, dysbindin is involved in neurite outgrowth and regulation of N-methyl-D-aspartate receptor (NMDAR) signaling...
July 31, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/30060843/altered-nuclear-expression-of-the-deubiquitylase-bap1-cannot-be-used-as-a-prognostic-marker-for-canine-melanoma
#13
N Jama, N Farquhar, Z Butt, S E Coupland, J J Sacco, T Scase, A B Fielding, J M Coulson, H Kalirai, D R Killick
BRCA1-associated protein-1 (BAP1) is a nuclear localized deubiquitylating enzyme that belongs to the ubiquitin c-terminal hydrolase subfamily. The encoded protein is highly homologous between man and dogs, suggesting a functional significance preserved by evolution. BAP1 has multiple properties, including tumour suppressor activity. Loss of BAP1 function is implicated in the oncogenesis of several types of cancers including uveal, mucosal and some cutaneous melanomas in humans, as well as in mesothelioma. In this study we investigate the significance of BAP1 in canine melanoma...
July 2018: Journal of Comparative Pathology
https://www.readbyqxmd.com/read/30057029/de-novo-variants-in-the-f-box-protein-fbxo11-in-20-individuals-with-a-variable-neurodevelopmental-disorder
#14
Anne Gregor, Lynette G Sadleir, Reza Asadollahi, Silvia Azzarello-Burri, Agatino Battaglia, Lilian Bomme Ousager, Paranchai Boonsawat, Ange-Line Bruel, Rebecca Buchert, Eduardo Calpena, Benjamin Cogné, Bruno Dallapiccola, Felix Distelmaier, Frances Elmslie, Laurence Faivre, Tobias B Haack, Victoria Harrison, Alex Henderson, David Hunt, Bertrand Isidor, Pascal Joset, Satoko Kumada, Augusta M A Lachmeijer, Melissa Lees, Sally Ann Lynch, Francisco Martinez, Naomichi Matsumoto, Carey McDougall, Heather C Mefford, Noriko Miyake, Candace T Myers, Sébastien Moutton, Addie Nesbitt, Antonio Novelli, Carmen Orellana, Anita Rauch, Monica Rosello, Ken Saida, Avni B Santani, Ajoy Sarkar, Ingrid E Scheffer, Marwan Shinawi, Katharina Steindl, Joseph D Symonds, Elaine H Zackai, André Reis, Heinrich Sticht, Christiane Zweier
Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies...
August 2, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/30054151/serum-gfap-and-uch-l1-for-prediction-of-absence-of-intracranial-injuries-on-head-ct-alert-tbi-a-multicentre-observational-study
#15
Jeffrey J Bazarian, Peter Biberthaler, Robert D Welch, Lawrence M Lewis, Pal Barzo, Viktoria Bogner-Flatz, P Gunnar Brolinson, Andras Büki, James Y Chen, Robert H Christenson, Dallas Hack, J Stephen Huff, Sandeep Johar, J Dedrick Jordan, Bernd A Leidel, Tobias Lindner, Elizabeth Ludington, David O Okonkwo, Joseph Ornato, W Frank Peacock, Kara Schmidt, Joseph A Tyndall, Arastoo Vossough, Andy S Jagoda
BACKGROUND: More than 50 million people worldwide sustain a traumatic brain injury (TBI) annually. Detection of intracranial injuries relies on head CT, which is overused and resource intensive. Blood-based brain biomarkers hold the potential to predict absence of intracranial injury and thus reduce unnecessary head CT scanning. We sought to validate a test combining ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), at predetermined cutoff values, to predict traumatic intracranial injuries on head CT scan acutely after TBI...
July 24, 2018: Lancet Neurology
https://www.readbyqxmd.com/read/30040487/rybp-modulates-stability-and-function-of-ring1b-through-targeting-ube3a
#16
Meng Li, Shiqiang Zhang, Wen Zhao, Congcong Hou, Xiaoli Ma, Xuekun Li, Bingren Huang, Hong Chen, Deng Chen
Ring1 and yin yang 1-binding protein (RYBP) are central components of noncanonical polycomb-repressive complex 1 (nc-PRC1), which represses target gene expression and is required for normal organismal development. However, the molecular function of RYBP in this complex is obscure. In this study, we showed that RYBP inhibits the polyubiquitination-mediated proteasomal degradation of Ring1B independently of its ubiquitin (Ub)-protein isopeptide ligase (E3) ligase activity, leading to its stabilization and increased catalytic activity toward monoubiquitination of histone H2A at lysine 119...
July 24, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/30037883/extending-chemical-perturbations-of-the-ubiquitin-fitness-landscape-in-a-classroom-setting-reveals-new-constraints-on-sequence-tolerance
#17
David Mavor, Kyle A Barlow, Daniel Asarnow, Yuliya Birman, Derek Britain, Weilin Chen, Evan M Green, Lillian R Kenner, Bruk Mensa, Leanna S Morinishi, Charlotte A Nelson, Erin M Poss, Pooja Suresh, Ruilin Tian, Taylor Arhar, Beatrice E Ary, David P Bauer, Ian D Bergman, Rachel M Brunetti, Cynthia M Chio, Shizhong A Dai, Miles S Dickinson, Susanna K Elledge, Cole V M Helsell, Nathan L Hendel, Emily Kang, Nadja Kern, Matvei S Khoroshkin, Lisa L Kirkemo, Greyson R Lewis, Kevin Lou, Wesley M Marin, Alison M Maxwell, Peter F McTigue, Douglas Myers-Turnbull, Tamas L Nagy, Andrew M Natale, Keely Oltion, Sergei Pourmal, Gabriel K Reder, Nicholas J Rettko, Peter J Rohweder, Daniel M C Schwarz, Sophia K Tan, Paul V Thomas, Ryan W Tibble, Jason P Town, Mary K Tsai, Fatima S Ugur, Douglas R Wassarman, Alexander M Wolff, Taia S Wu, Derek Bogdanoff, Jennifer Li, Kurt S Thorn, Shane O'Conchúir, Danielle L Swaney, Eric D Chow, Hiten D Madhani, Sy Redding, Daniel N Bolon, Tanja Kortemme, Joseph L DeRisi, Martin Kampmann, James S Fraser
Although the primary protein sequence of ubiquitin (Ub) is extremely stable over evolutionary time, it is highly tolerant to mutation during selection experiments performed in the laboratory. We have proposed that this discrepancy results from the difference between fitness under laboratory culture conditions and the selective pressures in changing environments over evolutionary timescales. Building on our previous work (Mavor et al., 2016), we used deep mutational scanning to determine how twelve new chemicals (3-Amino-1,2,4-triazole, 5-fluorocytosine, Amphotericin B, CaCl2 , Cerulenin, Cobalt Acetate, Menadione, Nickel Chloride, p-Fluorophenylalanine, Rapamycin, Tamoxifen, and Tunicamycin) reveal novel mutational sensitivities of ubiquitin residues...
July 23, 2018: Biology Open
https://www.readbyqxmd.com/read/30031030/functional-analysis-of-fanconi-anemia-mutations-in-china
#18
Niu Li, Lixia Ding, Benshang Li, Jian Wang, Alan D D'Andrea, Jing Chen
Fanconi anemia (FA) is a rare recessive disease characterized by progressive bone marrow failure, congenital abnormalities, and increased incidence of cancers. To date, mutations in 22 genes can cause FA or an FA-like phenotype. In China, in addition to clinical information, FA diagnosis primarily relies on genetic sequencing because the chromosome breakage test is rarely performed. Here, we employed multiple genetic diagnostic tools (DNA sequencing, multiplex ligation-dependent probe amplification, and chromosome microarray) and a variant-based functional assay platform to investigate the genetic cause in 25 Chinese suspected FA patients...
July 19, 2018: Experimental Hematology
https://www.readbyqxmd.com/read/30027154/diacylglycerol-kinase-%C3%AE-dgk%C3%AE-and-casitas-b-lineage-proto-oncogene-b-deficient-mice-have-similar-functional-outcomes-in-t-cells-but-dgk%C3%AE-deficient-mice-have-increased-t-cell-activation-and-tumor-clearance
#19
Erin M Wesley, Gang Xin, Donna McAllister, Subramaniam Malarkannan, Debra K Newman, Michael B Dwinell, Weiguo Cui, Bryon D Johnson, Matthew J Riese
Targeting negative regulators downstream of the T cell receptor (TCR) represents a novel strategy to improve cancer immunotherapy. Two proteins that serve as critical inhibitory regulators downstream of the TCR are diacylglycerol kinase ζ (DGKζ), a regulator of Ras and PKC-θ signaling, and Casitas b-lineage proto-oncogene b (Cbl-b), an E3 ubiquitin ligase that predominantly regulates PI(3)K signaling. We sought to compare the signaling and functional effects that result from deletion of DGKζ, Cbl-b, or both (double knockout, DKO) in T cells, and to evaluate tumor responses generated in a clinically relevant orthotopic pancreatic tumor model...
April 1, 2018: ImmunoHorizons
https://www.readbyqxmd.com/read/30026309/small-molecule-inhibitors-reveal-an-indispensable-scaffolding-role-of-ripk2-in-nod2-signaling
#20
Matous Hrdinka, Lisa Schlicher, Bing Dai, Daniel M Pinkas, Joshua C Bufton, Sarah Picaud, Jennifer A Ward, Catherine Rogers, Chalada Suebsuwong, Sameer Nikhar, Gregory D Cuny, Kilian Vm Huber, Panagis Filippakopoulos, Alex N Bullock, Alexei Degterev, Mads Gyrd-Hansen
RIPK2 mediates inflammatory signaling by the bacteria-sensing receptors NOD1 and NOD2. Kinase inhibitors targeting RIPK2 are a proposed strategy to ameliorate NOD-mediated pathologies. Here, we reveal that RIPK2 kinase activity is dispensable for NOD2 inflammatory signaling and show that RIPK2 inhibitors function instead by antagonizing XIAP-binding and XIAP-mediated ubiquitination of RIPK2. We map the XIAP binding site on RIPK2 to the loop between β2 and β3 of the N-lobe of the kinase, which is in close proximity to the ATP-binding pocket...
July 19, 2018: EMBO Journal
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