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Kalyan S Chakrabarti, Jess Li, Ranabir Das, R Andrew Byrd
Conformational dynamics plays a fundamental role in molecular recognition and activity in enzymes. The ubiquitin-conjugating enzyme (E2) Ube2g2 functions with the ubiquitin ligase (E3) gp78 to assemble poly-ubiquitin chains on target substrates. Two domains in gp78, RING and G2BR, bind to two distant regions of Ube2g2, and activate it for ubiquitin (Ub) transfer. G2BR increases the affinity between the RING and Ube2g2 by 50-fold, while the RING catalyzes the transfer of Ub from the Ube2g2∼Ub conjugate. How G2BR and RING activate Ube2g2 is unclear...
April 13, 2017: Structure
Nazli Khodayari, Rejean Liqun Wang, George Marek, Karina Krotova, Mariana Kirst, Chen Liu, Farshid Rouhani, Mark Brantly
Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder characterized by early-onset emphysema and liver disease. The most common disease-causing mutation is a single amino acid substitution (Glu/Lys) at amino acid 342 of the mature protein, resulting in disruption of the 290-342 salt bridge (an electrophoretic abnormality defining the mutation [Z allele, or ZAAT]), protein misfolding, polymerization, and accumulation in the endoplasmic reticulum of hepatocytes and monocytes. The Z allele causes a toxic gain of function, and the E3 ubiquitin ligase gp78 promotes degradation and increased solubility of endogenous ZAAT...
2017: PloS One
Rukmini Mukherjee, Aneesha Das, Saikat Chakrabarti, Oishee Chakrabarti
The ubiquitination status of proteins and intracellular calcium levels are two factors which keep changing inside any living cell. These two events appear to be independent of each other but recent experimental evidences show that ubiquitination of cellular proteins are influenced by calcium, Calmodulin, Calmodulin-dependent kinase II and other proteins of calcium dependent pathways. E3 ligases like Nedd4, SCF complex, APC, GP78 and ITCH are important regulators of calcium mediated processes. A bioinformatics analysis to inspect sequences and interacting partners of 242 candidate E3 ligases show the presence of calcium and/or Calmodulin binding motifs/domains within their sequences...
March 8, 2017: Biochimica et Biophysica Acta
Long Wang, Hua-Cheng Li, Jian Zhou, Bo Yang, Cheng-Dong Qiao, Yong-Ming Liu, Zheng Zhang
OBJECTIVE: To study the correlation between GP78 gene polymorphism and blood fat, blood glucose, blood pressure as well as coronary atherosclerotic heart disease. METHODS: 72 patients with coronary atherosclerotic heart disease were selected as the observation group. 68 healthy participants were selected as the control group. The gp78 gene polymorphism of both groups was studied by the method of polymerase chain reaction-restriction fragment length polymorphism (RFLP)...
February 14, 2017: Hellenic Journal of Cardiology: HJC, Hellēnikē Kardiologikē Epitheōrēsē
Yalcin Erzurumlu, Petek Ballar
The endoplasmic reticulum (ER) comprises thirty percent of the newly translated proteins in eukaryotic cells. The quality control mechanism within the ER distinguishes between properly and improperly folded proteins and ensures that unwanted proteins are retained in the ER and subsequently degraded through ER-associated degradation (ERAD). Besides cleaning of misfolded proteins ERAD is also important for physiological processes by regulating the abundance of normal proteins of the ER. Thus it is important to unreveal the regulation patterns of ERAD...
January 16, 2017: Scientific Reports
Na Li, Zhang-Sen Zhou, Yang Shen, Jie Xu, Hong-Hua Miao, Ying Xiong, Feng Xu, Bo-Liang Li, Jie Luo, Bao-Liang Song
Obesity is a critical risk factor for hepatocellular carcinoma (HCC). However, it remains unknown whether inhibition of de novo lipid biosynthesis can suppress HCC. In this study, we blocked the sterol regulatory element binding protein (SREBP) pathway, one of the key determinants of lipid homeostasis, by ablating gp78 or SCAP in hepatocytes as well as by administering a chemical compound called betulin. We found that either genetically or pharmacologically inhibiting the SREBP pathway dramatically reduced diethylnitrosamine (DEN)-induced HCC progression through down-regulating tumor promoting cytokines including IL-6, TNF-α and IL-1β...
December 27, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
María-José Barrera, Sergio Aguilera, Isabel Castro, Juan Cortés, Verónica Bahamondes, Andrew F G Quest, Claudio Molina, Sergio González, Marcela Hermoso, Ulises Urzúa, Cecilia Leyton, María-Julieta González
Salivary gland (SG) acinar-cells are susceptible to endoplasmic reticulum (ER) stress related to their secretory activity and the complexity of synthesized secretory products. SGs of Sjögren's syndrome patients (SS)-patients show signs of inflammation and altered proteostasis, associated with low IRE1α/XBP-1 pathway activity without avert increases in apoptosis. Acinar-cells may avoid apoptosis by activation of the ATF6α pathway and ER-associated protein degradation (ERAD). The aim of this study was to evaluate the role of pro-inflammatory cytokines in ATF6α pathway/ERAD activation and cell viability in labial salivary glands (LSG) of SS-patients...
July 23, 2016: Journal of Autoimmunity
Jia Jia Lim, Youngjin Lee, Tue Tu Ly, Jung Youn Kang, Jung-Gyu Lee, Jun Yop An, Hyung-Seop Youn, Kyoung Ryoung Park, Tae Gyun Kim, Jin Kuk Yang, Youngsoo Jun, Soo Hyun Eom
RHBDL4 is an active rhomboid that specifically recognizes and cleaves atypical, positively charged transmembrane endoplasmic reticulum-associated degradation (ERAD) substrates. Interaction of valosin-containing protein (p97/VCP) and RHBDL4 is crucial to retrotranslocate polyubiquitinated substrates for ERAD pathway. Here, we report the first complex structure of VCP-binding motif (VBM) with p97 N-terminal domain (p97N) at 1.88 Å resolution. Consistent with p97 adaptor proteins including p47-ubiquitin regulatory X (UBX), gp78-VCP-interacting motif (VIM), OTU1-UBX-like element, and FAF1-UBX, RHBDL4 VBM also binds at the interface between the two lobes of p97N...
September 15, 2016: Biochemical Journal
Yupeng Zhao, Ting Zhang, Huanhuan Huo, Yihong Ye, Yanfen Liu
The endoplasmic reticulum (ER) network comprises sheets and tubules that are connected by dynamic three-way junctions. Lunapark (Lnp) localizes to and stabilizes ER three-way junctions by antagonizing the small GTPase Atlastin, but how Lnp shapes the ER network is unclear. Here, we used an affinity purification approach and mass spectrometry to identify Lnp as an interacting partner of the ER protein quality control ubiquitin ligase gp78. Accordingly, Lnp purified from mammalian cells has a ubiquitin ligase activity in vitro Intriguingly, biochemical analyses show that this activity can be attributed not only to associated ubiquitin ligase, but also to an intrinsic ubiquitin ligase activity borne by Lnp itself...
August 26, 2016: Journal of Biological Chemistry
Sung-Mi Kim, YongQiang Wang, Noushin Nabavi, Yi Liu, Maria Almira Correia
The endoplasmic reticulum (ER)-anchored hepatic cytochromes P450 (P450s) are enzymes that metabolize endo- and xenobiotics i.e. drugs, carcinogens, toxins, natural and chemical products. These agents modulate liver P450 content through increased synthesis or reduction via inactivation and/or proteolytic degradation, resulting in clinically significant drug-drug interactions. P450 proteolytic degradation occurs via ER-associated degradation (ERAD) involving either of two distinct routes: Ubiquitin (Ub)-dependent 26S proteasomal degradation (ERAD/UPD) or autophagic lysosomal degradation (ERAD/ALD)...
August 2016: Drug Metabolism Reviews
Fengyi Gao, Yongliang Shang, Weixiao Liu, Wei Li
Polyubiquitin chain linkage specificity or topology is essential for its role in diverse cellular processes. Previous studies pay more attentions to the linkage specificity of the first ubiquitin moieties, whereas, little is known about the editing mechanism of linkage specificity in longer polyubiquitin chains. gp78 and its cognate E2-Ube2g2 catalyze lysine48 (K48)-linked polyubiquitin chains to promote the degradation of targeted proteins. Here, we show that the linkage specificity of the entire polyubiquitin chain is determined by the conjugation manner of the first ubiquitin molecule but not the following ones...
May 13, 2016: Biochemical and Biophysical Research Communications
Fabien Llambi, Yue-Ming Wang, Bernadette Victor, Mao Yang, Desiree M Schneider, Sébastien Gingras, Melissa J Parsons, Janet H Zheng, Scott A Brown, Stéphane Pelletier, Tudor Moldoveanu, Taosheng Chen, Douglas R Green
The mitochondrial pathway of apoptosis is initiated by mitochondrial outer membrane permeabilization (MOMP). The BCL-2 family effectors BAX and BAK are thought to be absolutely required for this process. Here, we report that BCL-2 ovarian killer (BOK) is a bona fide yet unconventional effector of MOMP that can trigger apoptosis in the absence of both BAX and BAK. However, unlike the canonical effectors, BOK appears to be constitutively active and unresponsive to antagonistic effects of the antiapoptotic BCL-2 proteins...
April 7, 2016: Cell
Rukmini Mukherjee, Oishee Chakrabarti
Cellular quality control provides an efficient surveillance system to regulate mitochondrial turnover. This study elucidates a new interaction between the cytosolic E3 ligase mahogunin RING finger 1 (MGRN1) and the endoplasmic reticulum (ER) ubiquitin E3 ligase GP78 (also known as AMFR). Loss of Mgrn1 function has been implicated in late-onset spongiform neurodegeneration and congenital heart defects, among several developmental defects. Here, we show that MGRN1 ubiquitylates GP78 in trans through non-canonical K11 linkages...
February 15, 2016: Journal of Cell Science
Giuseppe Lucarelli, Monica Rutigliano, Francesca Sanguedolce, Vanessa Galleggiante, Andrea Giglio, Simona Cagiano, Pantaleo Bufo, Eugenio Maiorano, Domenico Ribatti, Elena Ranieri, Margherita Gigante, Loreto Gesualdo, Matteo Ferro, Ottavio de Cobelli, Carlo Buonerba, Giuseppe Di Lorenzo, Sabino De Placido, Silvano Palazzo, Carlo Bettocchi, Pasquale Ditonno, Michele Battaglia
Glucose-6-phosphate isomerase (GPI), also known as phosphoglucose isomerase, was initially identified as the second glycolytic enzyme that catalyzes the interconversion of glucose-6-phosphate to fructose-6-phosphate. Later studies demonstrated that GPI was the same as the autocrine motility factor (AMF), and that it mediates its biological effects through the interaction with its surface receptor (AMFR/gp78). In this study, we assessed the role of GPI/AMF as a prognostic factor for clear cell renal cell carcinoma (ccRCC) cancer-specific (CSS) and progression-free survival (PFS)...
November 2015: Medicine (Baltimore)
Kang Tian, Weiliang Zhong, Xifu Zheng, Jinrui Zhang, Pixu Liu, Weiguo Zhang, Han Liu
Cartilage defect is an intractable clinical problem. Therapeutic strategies for cartilage repair are far from optimal due to poor proliferation capacity of chondrocytes. Autologous chondrocyte implantation is a cell based therapy that uses in vitro amplified healthy chondrocytes from the patient. However, chondrocyte dedifferentiation during in vitro culture limits its application. Neuroleukin (NLK) is a multifunctional protein that stimulates cell growth and migration, together with its receptor autocrine motility factor receptor (AMFR, also called gp78)...
October 13, 2015: Scientific Reports
Ting Zhang, Yue Xu, Yanfen Liu, Yihong Ye
Eukaryotic cells eliminate misfolded proteins from the endoplasmic reticulum (ER) via a conserved process termed ER-associated degradation (ERAD). Central regulators of the ERAD system are membrane-bound ubiquitin ligases, which are thought to channel misfolded proteins through the ER membrane during retrotranslocation. Hrd1 and gp78 are mammalian ubiquitin ligases homologous to Hrd1p, an ubiquitin ligase essential for ERAD in Saccharomyces cerevisiae. However, the functional relevance of these proteins to Hrd1p is unclear...
December 1, 2015: Molecular Biology of the Cell
Lei Li, Guang Gao, Jay Shankar, Bharat Joshi, Leonard J Foster, Ivan R Nabi
Gp78 is an ERAD-associated E3 ubiquitin ligase that induces degradation of the mitofusin mitochondrial fusion proteins and mitochondrial fission. Gp78 is localized throughout the ER; however, the anti-Gp78 3F3A monoclonal antibody (mAb) recognizes Gp78 selectively in mitochondria-associated ER domains. Epitope mapping localized the epitope of 3F3A and a commercial anti-Gp78 mAb to an 8-amino acid motif (533-541) in mouse Gp78 isoform 2 that forms part of a highly conserved 41-amino acid region containing 14-3-3- and WW-binding domains and a p38 MAP kinase (p38 MAPK) consensus site on Ser-538 (S538)...
November 1, 2015: Molecular Biology of the Cell
Jin Chai, Shi-Ying Cai, Xiaocong Liu, Wei Lian, Sheng Chen, Liangjun Zhang, Xinchan Feng, Ying Cheng, Xiaochong He, Yu He, Lei Chen, Rongquan Wang, Huaizhi Wang, James L Boyer, Wensheng Chen
BACKGROUND & AIMS: Multidrug resistance-associated protein 2 (MRP2) excretes conjugated organic anions including bilirubin and bile acids. Malfunction of MRP2 leads to jaundice in patients. Studies in rodents indicate that Radixin plays a critical role in determining Mrp2 canalicular membrane expression. However, it is not known how human hepatic MRP2 expression is regulated in cholestasis. METHODS: We assessed liver MRP2 expression in patients with obstructive cholestasis caused by gallstone blockage of bile ducts, and investigated the regulatory mechanism in HepG2 cells...
December 2015: Journal of Hepatology
(no author information available yet)
No abstract text is available yet for this article.
2015: Lipids in Health and Disease
Katsunori Nonogaki, Tomoe Yamazaki, Mari Murakami, Takao Kaji
Fibroblast growth factor (FGF) 21 is a mediator of glucose and lipid metabolism. Although exogenous administration of FGF21 exerts beneficial effects on glucose and lipid metabolism, circulating FGF21 levels are elevated in ob/ob and db/db mice, diet-induced obese mice and obese human. Here we show that ingestion of eicosapentaenoic acid (EPA) for 6 days after individually-housing significantly suppressed the hyperglycemia and hypertriglyceridemia associated with decreases in plasma insulin and FGF21 levels in KKA(y) mice while having no effects on food intake, body weight or plasma active GLP-1 levels...
August 21, 2015: Biochemical and Biophysical Research Communications
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