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Young Dong Yoo, Su Ran Mun, Chang Hoon Ji, Ki Woon Sung, Keum Young Kang, Ah Jung Heo, Su Hyun Lee, Jee Young An, Joonsung Hwang, Xiang-Qun Xie, Aaron Ciechanover, Bo Yeon Kim, Yong Tae Kwon
The conjugation of amino acids to the protein N termini is universally observed in eukaryotes and prokaryotes, yet its functions remain poorly understood. In eukaryotes, the amino acid l-arginine (l-Arg) is conjugated to N-terminal Asp (Nt-Asp), Glu, Gln, Asn, and Cys, directly or associated with posttranslational modifications. Following Nt-arginylation, the Nt-Arg is recognized by UBR boxes of N-recognins such as UBR1, UBR2, UBR4/p600, and UBR5/EDD, leading to substrate ubiquitination and proteasomal degradation via the N-end rule pathway...
March 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
Kwang-Dong Choi, Ji-Soo Kim, Hyo-Jung Kim, Ileok Jung, Seong-Hae Jeong, Seung-Han Lee, Dong Uk Kim, Sang-Ho Kim, Seo Young Choi, Jin-Hong Shin, Dae-Seong Kim, Kyung-Pil Park, Hyang-Sook Kim, Jae-Hwan Choi
Episodic ataxia (EA) is a rare neurological condition characterized by recurrent spells of truncal ataxia and incoordination. Five genes (KCNA1, CACNA1A, CACNB4, SLC1A3, and UBR4) have been linked to EA. Despite extensive efforts to genetically diagnose EA, many patients remain still undiagnosed. Whole-exome sequencing was carried out in 39 Korean patients with EA to identify pathogenic mutations of the five known EA genes. We also evaluated 40 candidate genes that cause EA as a secondary phenotype or cerebellar ataxia...
October 23, 2017: Scientific Reports
Jinhui Wang, Daofei Qu, Jinghong An, Guoming Yuan, Yufu Liu
Glaucoma is characterized as a visual field defect, which is the second most common cause of blindness. The present study performed an integrated analysis of microarray studies of glaucoma derived from Gene Expression Omnibus (GEO). Following the identification of the differentially expressed genes (DEGs) in glaucoma compared with normal control (NC) tissues, the functional annotation, glaucoma‑specific protein‑protein interaction (PPI) network and transcriptional regulatory network constructions were performed...
December 2017: Molecular Medicine Reports
Dorota Monies, Mohamed Abouelhoda, Moeenaldeen AlSayed, Zuhair Alhassnan, Maha Alotaibi, Husam Kayyali, Mohammed Al-Owain, Ayaz Shah, Zuhair Rahbeeni, Mohammad A Al-Muhaizea, Hamad I Alzaidan, Edward Cupler, Saeed Bohlega, Eissa Faqeih, Maha Faden, Banan Alyounes, Dyala Jaroudi, Ewa Goljan, Hadeel Elbardisy, Asma Akilan, Renad Albar, Hesham Aldhalaan, Shamshad Gulab, Aziza Chedrawi, Bandar K Al Saud, Wesam Kurdi, Nawal Makhseed, Tahani Alqasim, Heba Y El Khashab, Hamoud Al-Mousa, Amal Alhashem, Imaduddin Kanaan, Talal Algoufi, Khalid Alsaleem, Talal A Basha, Fathiya Al-Murshedi, Sameena Khan, Adila Al-Kindy, Maha Alnemer, Sami Al-Hajjar, Suad Alyamani, Hasan Aldhekri, Ali Al-Mehaidib, Rand Arnaout, Omar Dabbagh, Mohammad Shagrani, Dieter Broering, Maha Tulbah, Amal Alqassmi, Maisoon Almugbel, Mohammed AlQuaiz, Abdulaziz Alsaman, Khalid Al-Thihli, Raashda A Sulaiman, Wajeeh Al-Dekhail, Abeer Alsaegh, Fahad A Bashiri, Alya Qari, Suzan Alhomadi, Hisham Alkuraya, Mohammed Alsebayel, Muddathir H Hamad, Laszlo Szonyi, Faisal Abaalkhail, Sulaiman M Al-Mayouf, Hamad Almojalli, Khalid S Alqadi, Hussien Elsiesy, Taghreed M Shuaib, Mohammed Zain Seidahmed, Ibraheem Abosoudah, Hana Akleh, Abdulaziz AlGhonaium, Turki M Alkharfy, Fuad Al Mutairi, Wafa Eyaid, Abdullah Alshanbary, Farrukh R Sheikh, Fahad I Alsohaibani, Abdullah Alsonbul, Saeed Al Tala, Soher Balkhy, Randa Bassiouni, Ahmed S Alenizi, Maged H Hussein, Saeed Hassan, Mohamed Khalil, Brahim Tabarki, Saad Alshahwan, Amira Oshi, Yasser Sabr, Saad Alsaadoun, Mustafa A Salih, Sarar Mohamed, Habiba Sultana, Abdullah Tamim, Moayad El-Haj, Saif Alshahrani, Dalal K Bubshait, Majid Alfadhel, Tariq Faquih, Mohamed El-Kalioby, Shazia Subhani, Zeeshan Shah, Nabil Moghrabi, Brian F Meyer, Fowzan S Alkuraya
In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016-December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants...
August 2017: Human Genetics
Stefan S Rudel, Florian Kraus
Herein we describe convenient lab scale syntheses of several uranium(iv) halides of high purity by reaction of AlX3 (X = Cl, Br and I) with UO2 , which is readily available by reduction of uranyl salts like UO2 (NO3 )2 ·6H2 O. UCl4 , UBr4 , and UI4 are obtained in the form of aggregates of large single crystals. Their identities and purity were checked by powder X-ray diffraction, IR spectroscopy and elemental analysis. The syntheses introduced here avoid the need for pure metallic uranium and are based on more readily available starting materials, UO2 , which does not even have to be pure, and the respective aluminium halide...
May 9, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
Anita Szalmás, Vjekoslav Tomaić, Om Basukala, Paola Massimi, Suruchi Mittal, József Kónya, Lawrence Banks
Activation of signaling pathways ensuring cell growth is essential for the proliferative competence of human papillomavirus (HPV)-infected cells. Tyrosine kinases and phosphatases are key regulators of cellular growth control pathways. A recently identified potential cellular target of HPV E7 is the cytoplasmic protein tyrosine phosphatase PTPN14, which is a potential tumor suppressor and is linked to the control of the Hippo and Wnt/beta-catenin signaling pathways. In this study, we show that the E7 proteins of both high-risk and low-risk mucosal HPV types can interact with PTPN14...
April 1, 2017: Journal of Virology
Xuedong Wang, Jiebo Lin, Fanghui Li, Cao Zhang, Jieyi Li, Caihong Wang, Randy A Dahlgren, Hongqin Zhang, Huili Wang
Long non-coding RNAs (lncRNAs) have attracted considerable research interest, but so far no data are available on the roles of lncRNAs and their target genes under chronic β-diketone antibiotic (DKAs) exposure to zebrafish (Danio rerio). Herein, we identified 1.66, 3.07 and 3.36×10(4) unique lncRNAs from the 0, 6.25 and 12.5mg/L DKA treatment groups, respectively. In comparison with the control group, the 6.25 and 12.5mg/L treatments led to up-regulation of 2064 and 2479 lncRNAs, and down-regulation of 778 and 954 lncRNAs, respectively...
January 2017: Aquatic Toxicology
Elizabeth A White, Karl Münger, Peter M Howley
UNLABELLED: The major transformation activity of the high-risk human papillomaviruses (HPV) is associated with the E7 oncoprotein. The interaction of HPV E7 with retinoblastoma family proteins is important for several E7 activities; however, this interaction does not fully account for the high-risk E7-specific cellular immortalization and transformation activities. We have determined that the cellular non-receptor protein tyrosine phosphatase PTPN14 interacts with HPV E7 from many genus alpha and beta HPV types...
September 20, 2016: MBio
Dariel Ashton-Beaucage, Caroline Lemieux, Christian M Udell, Malha Sahmi, Samuel Rochette, Marc Therrien
RAS-induced MAPK signaling is a central driver of the cell proliferation apparatus. Disruption of this pathway is widely observed in cancer and other pathologies. Consequently, considerable effort has been devoted to understanding the mechanistic aspects of RAS-MAPK signal transmission and regulation. While much information has been garnered on the steps leading up to the activation and inactivation of core pathway components, comparatively little is known on the mechanisms controlling their expression and turnover...
August 2016: PLoS Biology
Alesha Grant, Sanket S Ponia, Shashank Tripathi, Vinod Balasubramaniam, Lisa Miorin, Marion Sourisseau, Megan C Schwarz, Mari Paz Sánchez-Seco, Matthew J Evans, Sonja M Best, Adolfo García-Sastre
The ongoing epidemic of Zika virus (ZIKV) illustrates the importance of flaviviruses as emerging human pathogens. All vector-borne flaviviruses studied thus far have to overcome type I interferon (IFN) to replicate and cause disease in vertebrates. The mechanism(s) by which ZIKV antagonizes IFN signaling is unknown. Here, we report that the nonstructural protein NS5 of ZIKV and other flaviviruses examined could suppress IFN signaling, but through different mechanisms. ZIKV NS5 expression resulted in proteasomal degradation of the IFN-regulated transcriptional activator STAT2 from humans, but not mice, which may explain the requirement for IFN deficiency to observe ZIKV-induced disease in mice...
June 8, 2016: Cell Host & Microbe
Markus M Rinschen, Puneet Bharill, Xiongwu Wu, Priyanka Kohli, Matthäus J Reinert, Oliver Kretz, Isabel Saez, Bernhard Schermer, Martin Höhne, Malte P Bartram, Sriram Aravamudhan, Bernard R Brooks, David Vilchez, Tobias B Huber, Roman-Ulrich Müller, Marcus Krüger, Thomas Benzing
The PHB-domain protein podocin maintains the renal filtration barrier and its mutation is an important cause of hereditary nephrotic syndrome. Podocin and its Caenorhabditis elegans orthologue MEC-2 have emerged as key components of mechanosensitive membrane protein signalling complexes. Whereas podocin resides at a specialized cell junction at the podocyte slit diaphragm, MEC-2 is found in neurons required for touch sensitivity. Here, we show that the ubiquitin ligase Ubr4 is a key component of the podocin interactome purified both from cultured podocytes and native glomeruli...
April 1, 2016: Human Molecular Genetics
Inês S Amorim, Nadia L Mitchell, David N Palmer, Stephen J Sawiak, Roger Mason, Thomas M Wishart, Thomas H Gillingwater
AIMS: Synapses represent a major pathological target across a broad range of neurodegenerative conditions. Recent studies addressing molecular mechanisms regulating synaptic vulnerability and degeneration have relied heavily on invertebrate and mouse models. Whether similar molecular neuropathological changes underpin synaptic breakdown in large animal models and in human patients with neurodegenerative disease remains unclear. We therefore investigated whether molecular regulators of synaptic pathophysiology, previously identified in Drosophila and mouse models, are similarly present and modified in the brain of sheep with CLN5 Batten disease...
November 2015: Brain and Behavior
Shashank Tripathi, Marie O Pohl, Yingyao Zhou, Ariel Rodriguez-Frandsen, Guojun Wang, David A Stein, Hong M Moulton, Paul DeJesus, Jianwei Che, Lubbertus C F Mulder, Emilio Yángüez, Dario Andenmatten, Lars Pache, Balaji Manicassamy, Randy A Albrecht, Maria G Gonzalez, Quy Nguyen, Abraham Brass, Stephen Elledge, Michael White, Sagi Shapira, Nir Hacohen, Alexander Karlas, Thomas F Meyer, Michael Shales, Andre Gatorano, Jeffrey R Johnson, Gwen Jang, Tasha Johnson, Erik Verschueren, Doug Sanders, Nevan Krogan, Megan Shaw, Renate König, Silke Stertz, Adolfo García-Sastre, Sumit K Chanda
Several systems-level datasets designed to dissect host-pathogen interactions during influenza A infection have been reported. However, apparent discordance among these data has hampered their full utility toward advancing mechanistic and therapeutic knowledge. To collectively reconcile these datasets, we performed a meta-analysis of data from eight published RNAi screens and integrated these data with three protein interaction datasets, including one generated within the context of this study. Further integration of these data with global virus-host interaction analyses revealed a functionally validated biochemical landscape of the influenza-host interface, which can be queried through a simplified and customizable web portal (http://www...
December 9, 2015: Cell Host & Microbe
Minghui Fu, Lihua Jiang, Yuanmei Li, Guohua Yan, Lijun Zheng, Peng Jinping
Eichhornia crassipes is an aquatic plant native to the Amazon River Basin. It has become a serious weed in freshwater habitats in rivers, lakes and reservoirs both in tropical and warm temperate areas worldwide. Some research has stated that it can be used for water phytoremediation, due to its strong assimilation of nitrogen and phosphorus, and the accumulation of heavy metals, and its growth and spread may play an important role in environmental ecology. In order to explore the molecular mechanism of E. crassipes to responses to nitrogen deficiency, we constructed forward and reversed subtracted cDNA libraries for E...
December 2014: Revista de Biología Tropical
Jenny H Hong, Lilia Kaustov, Etienne Coyaud, Tharan Srikumar, Janet Wan, Cheryl Arrowsmith, Brian Raught
RAD6 is a ubiquitin E2 protein with roles in a number of different biological processes. Here, using affinity purification coupled with mass spectrometry, we identify a number of new RAD6 binding partners, including the poorly characterized ubiquitin E3 ligases KCMF1 (potassium channel modulatory factor 1) and UBR4 (ubiquitin N-recognin domain-containing E3 ligase 4), a protein that can bind N-end rule substrates, and which was recently linked to lysosome-mediated degradation and autophagy. NMR, combined with in vivo and in vitro interaction mapping, demonstrate that the KCMF1 C terminus binds directly to RAD6, whereas N-terminal domains interact with UBR4 and other intracellular vesicle- and mitochondria-associated proteins...
March 2015: Molecular & Cellular Proteomics: MCP
Kari Parsons, Yoshihiro Nakatani, Minh Dang Nguyen
A decade ago, the large 600 kDa mammalian protein p600 (also known as UBR4) was discovered as a multifunctional protein with roles in anoikis, viral transformation and protein degradation. Recently, p600 has emerged as a critical protein in the mammalian brain with roles in neurogenesis, neuronal migration, neuronal signaling and survival. How p600 integrates these apparently unrelated functions to maintain tissue homeostasis and murine survival remains unclear. The common molecular basis underlying many of the actions of p600 suggests, however, certain conservation and transposition of these functions across systems...
March 2015: Cellular and Molecular Life Sciences: CMLS
Harrod H Ling, Christian Beaulé, Cheng-Kang Chiang, Ruijun Tian, Daniel Figeys, Hai-Ying M Cheng
Circadian rhythms of behavior and physiology are driven by the biological clock that operates endogenously but can also be entrained to the light-dark cycle of the environment. In mammals, the master circadian pacemaker is located in the suprachiasmatic nucleus (SCN), which is composed of individual cellular oscillators that are driven by a set of core clock genes interacting in transcriptional/translational feedback loops. Light signals can trigger molecular events in the SCN that ultimately impact on the phase of expression of core clock genes to reset the master pacemaker...
2014: PloS One
Camille Belzil, Tim Ramos, Kamon Sanada, Michael A Colicos, Minh Dang Nguyen
The large microtubule-associated/Ca(2+)-signalling protein p600 (also known as UBR4) is required for hippocampal neuronal survival upon Ca(2+) dyshomeostasis induced by glutamate treatment. During this process, p600 prevents aggregation of the Ca(2+)/calmodulin-dependent kinase IIα (CaMKIIα), a proxy of neuronal death, via direct binding to calmodulin in a microtubuleindependent manner. Using photoconductive stimulation coupled with live imaging of single neurons, we identified a distinct mechanism of prevention of CaMKIIα aggregation by p600...
September 2014: Cellular & Molecular Biology Letters
Koji Yamano, Richard J Youle
PINK1, a mitochondrial serine/threonine kinase, is the product of a gene mutated in an autosomal recessive form of Parkinson disease. PINK1 is constitutively degraded by an unknown mechanism and stabilized selectively on damaged mitochondria where it can recruit the E3 ligase PARK2/PARKIN to induce mitophagy. Here, we show that, under steady-state conditions, endogenous PINK1 is constitutively and rapidly degraded by E3 ubiquitin ligases UBR1, UBR2 and UBR4 through the N-end rule pathway. Following precursor import into mitochondria, PINK1 is cleaved in the transmembrane segment by a mitochondrial intramembrane protease PARL generating an N-terminal destabilizing amino acid and then retrotranslocates from mitochondria to the cytosol for N-end recognition and proteasomal degradation...
November 1, 2013: Autophagy
Judith Conroy, Paul McGettigan, Raymond Murphy, David Webb, Sinéad M Murphy, Blathnaid McCoy, Christine Albertyn, Dara McCreary, Cara McDonagh, Orla Walsh, Sallyann Lynch, Sean Ennis
Episodic ataxias (EAs) are rare neurological channelopathies that are characterized by spells of imbalance and a lack of co-ordination. There are seven clinically recognized EAs and multiple isolated cases. Five disease-causing genes have been identified to date. We describe a novel form of autosomal dominant EA in a large three-generation Irish family. This form of EA presents in early childhood with periods of unsteadiness generalized weakness and slurred speech during an attack, which may be triggered by physical tiredness or stress...
April 2014: European Journal of Human Genetics: EJHG
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