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Journal of Biological Chemistry

Casimiro Gerarduzzi, Anna de Polo, Xue-Song Liu, Manale El Kharbili, John B Little, Zhi-Min Yuan
Deregulated receptor tyrosine kinase (RTK) signaling is frequently associated with tumorigenesis and therapy resistance, but its underlying mechanisms still need to be elucidated. In this study we have shown that the RTK human epidermal growth factor receptor 4 (Her4, aka Erbb4) can inhibit the tumor suppressor p53 by regulating the MDMX-MDM2 complex stabilization. Upon activation by either overexpression of a constitutively active vector or ligand binding (Neuregulin-1), Her4 was able to stabilize the MDMX-MDM2 complex resulting in suppression of p53 transcriptional activity, as shown by p53 responsive element-driven luciferase assay and mRNA levels of p53 target genes...
October 24, 2016: Journal of Biological Chemistry
Yong-Kang Yang, Chao Yang, Waipan Chan, Zhaoquan Wang, Katelynn E Deibel, Joel L Pomerantz
The activation of NF-κB downstream of T Cell Receptor (TCR) engagement is a key signaling step required for normal lymphocyte function during the adaptive immune response. During TCR signaling, the adaptor protein Bcl10 is inducibly recruited to the CARD11 scaffold protein as part of a multicomponent complex that induces IKK kinase activity and NF-κB activation. Here we show that a consequence of this recruitment is the TCR-induced conjugation of Bcl10 with linear-linked polyubiquitin chains, to generate the signaling intermediate Lin(Ub)n-Bcl10, which is required for the association of Bcl10 with the NEMO subunit of the IKK complex...
October 24, 2016: Journal of Biological Chemistry
Jin Xie, Kun Cai, Hai-Xi Hu, Yong-Liang Jiang, Feng Yang, Peng-Fei Hu, Dong-Dong Cao, Wei-Fang Li, Yuxing Chen, Cong-Zhao Zhou
Invertases catalyze the hydrolysis of sucrose to glucose and fructose, thereby playing a key role in primary metabolism and plant development. According to the optimum pH, invertases are classified into acid invertases (Ac-Invs) and alkaline/neutral invertases (A/N-Invs), which share no sequence homology. Compared to Ac-Invs that have been extensively studied, the structure and catalytic mechanism of A/N-Invs remain unknown. Here we report the crystal structures of Anabaena alkaline invertase InvA, which was proposed to be the ancestor of modern plant A/N-Invs...
October 24, 2016: Journal of Biological Chemistry
Brie Sorrenson, Emmanuelle Cognard, Kathryn L Lee, Waruni C Dissanayake, Yanyun Fu, Weiping Han, William E Hughes, Peter R Shepherd
The processes regulating glucose-stimulated insulin secretion (GSIS) and its modulation by incretins in pancreatic β-cells are only partly understood. Here we investigate the involvement of β-catenin in these processes. Reducing β-catenin levels using siRNA knockdown attenuated GSIS in a range of β-cell models and blocked the ability of GLP-1 agonists and the depolarizing agent KCl to potentiate this. This could be mimicked in both β-cell models and isolated islets by short-term exposure to the β-catenin inhibitory drug pyrvinium...
October 24, 2016: Journal of Biological Chemistry
Heledd M Davies, Konstantinos Thalassinos, Andrew R Osborne
Repetitive low-complexity sequences, mostly assumed to have no function, are common in proteins that are exported by the malaria parasite into its host erythrocyte. We identify a group of exported proteins containing short lysine-rich tandemly repeated sequences that are sufficient to localise to the erythrocyte periphery where key virulence-related modifications to the plasma membrane and the underlying cytoskeleton are known to occur. Efficiency of targeting is dependent on repeat number, indicating that novel targeting modules could evolve by expansion of short lysine-rich sequences...
October 24, 2016: Journal of Biological Chemistry
An Li, Shanzhong Gong, Kenneth A Johnson
Previous measurements of the rates of polymerization and pyrophosphate release with DNA templates showed that pyrophosphate (PPi) dissociation was fast following nucleotide incorporation so that it did not contribute to enzyme specificity (kcat/Km). Here, kinetic parameters governing nucleotide incorporation and PPi release were determined using an RNA template. Compared with a DNA template of the same sequence, the rate of chemistry increased by up to 10-fold (250 vs 24 s-1) while the rate of PPi release decreased to approximate 58 s-1, so that PPi release became the rate-limiting step...
October 24, 2016: Journal of Biological Chemistry
An Li, Jiawen Li, Kenneth A Johnson
HIV Reverse Transcriptase (RT) plays a central role in viral replication and requires coordination of both polymerase and RNase H activities. Although this coordination is crucial in viral replication, whether a DNA/RNA hybrid can simultaneously engage both active sites has yet to be determined since structural and kinetic analyses have provided contradictory results. Single nucleotide incorporation and RNase H cleavage were examined using pre-steady-state kinetics with global data analysis. The results revealed three interconverting RT-DNA/RNA species: 43% were active for both sites, 27% showed only polymerase activity, and the remaining 30% were nonproductive...
October 24, 2016: Journal of Biological Chemistry
Bin Cheng, Yiwei Meng, Yanbing Cui, Chunfang Li, Fei Tao, Huijia Yin, Chunyu Yang, Ping Xu
Halomonas sp. Y2 is a halotolerant alkaliphilic strain from Na+-rich pulp mill wastewater with high alkalinity (pH >11.0). Transcriptome analysis of this isolate revealed this strain may use various transport systems for pH homeostasis. Especially, the genes encoding four putative Na+/H+ antiporters were differentially expressed upon acidic or alkaline conditions. Further evidence, from heterologous expression and mutant studies, suggested that Halomonas sp. Y2 employs its Na+/H+ antiporters in a labor division way to deal with saline and alkaline environments...
October 24, 2016: Journal of Biological Chemistry
Xing Liu, Xiaolian Cai, Bo Hu, Zhichao Mei, Dawei Zhang, Gang Ouyang, Jing Wang, Wei Zhang, Wuhan Xiao
FOXO3a, a member of the forkhead homeobox type O (FOXO) family of transcriptional factors, regulates cell survival in response to DNA damage, caloric restriction, and oxidative stress. The von Hippel-Lindau (VHL) tumor suppressor gene encodes a component of the E3 ubiquitin ligase complex that mediates hypoxia-inducible factor-α (HIF-α) degradation under aerobic conditions, thus acting as one of the key regulators of hypoxia signaling. However, whether FOXO3a impacts cellular hypoxia stress remains unknown...
October 24, 2016: Journal of Biological Chemistry
Jamie L Burgess, R Alan Burgess, Yalemi Morales, Jenna M Bouvang, Sean J Johnson, Nicholas E Dickenson
Like many Gram-negative pathogens, Shigella rely on a complex type three secretion system (T3SS) to inject effector proteins into host cells, take over host functions, and ultimately establish infection. Despite these critical roles, the energetics and regulatory mechanisms controlling the T3SS and pathogen virulence remain largely unclear. In this study, we present a series of high-resolution crystal structures of Spa47 and use the structures to model an activated Spa47 oligomer, finding that ATP hydrolysis may be supported by specific sidechain contributions from adjacent protomers within the complex...
October 21, 2016: Journal of Biological Chemistry
Shu-Yu Wu, Ping Zou, Alexandra W Fuller, Sanjay Mishra, Zhen Wang, Kevin L Schey, Hassane S Mchaourab
The refractivity and transparency of the ocular lens is dependent on the stability and solubility of the crystallins in the fiber cells. A number of mutations of lens crystallins have been associated with dominant cataracts in humans and mice. Of particular interest were γB- and γD-crystallin mutants linked to dominant cataracts in mouse models. While thermodynamically destabilized and aggregation-prone, these mutants were found to have weak affinity to the resident chaperone α-crystallin in vitro To better understand the mechanism of the cataract phenotype, we transgenically expressed different γD-crystallin mutants in the zebrafish lens, and observed a range of lens defects that arise primarily from the aggregation of the mutant proteins...
October 21, 2016: Journal of Biological Chemistry
Carolina Anazco, Alberto J Lopez-Jimenez, Mohamed Rafi, Lorenzo Vega-Montoto, Ming-Zhi Zhang, Billy G Hudson, Roberto M Vanacore
The 7S dodecamer is recognized as an important structural crosslinking domain of collagen IV networks that provide mechanical stability to basement membranes, a specialized form of extracellular matrix essential for the development and maintenance of tissue architecture. Although the 7S dodecamer is stabilized by covalent crosslinking, the molecular mechanism by which such crosslinks are formed has not been revealed. Here we aimed to identify the enzyme(s) that crosslinks the 7S dodecamer and characterize its expression in the kidney glomerulus...
October 21, 2016: Journal of Biological Chemistry
Sang-Ho Kwon, Sekyung Oh, Marisa Nacke, Keith E Mostov, Joshua H Lipschutz
Exosomes, 40-150 nm extracellular vesicles, transport biological macromolecules that mediate intercellular communications. While exosomes are known to originate from maturation of endosomes into multivesicular endosomes (MVEs; also known as multivesicular bodies, MVBs) with subsequent fusion of the MVEs with the plasma membrane, it remains unclear how cargos are selected for exosomal release. Using an inducible expression system for the exosome cargo protein GPRC5B and following its trafficking trajectory, we show here that newly synthesized GPRC5B protein accumulates in the Golgi complex prior to its release into exosomes...
October 20, 2016: Journal of Biological Chemistry
Katsuya Sato, Masashi Kimura, Kazue Sugiyama, Masashi Nishikawa, Yukio Okano, Hitoshi Nagaoka, Takahiro Nagase, Yukio Kitade, Hiroshi Ueda
PLEKHG2/FLJ00018 is a Gβγ-dependent guanine nucleotide exchange factor for the small GTPases Rac and Cdc42 and has been shown to mediate the signaling pathways leading to actin cytoskeleton reorganization. Here we showed that the zinc finger domain-containing protein four-and-a-half LIM domains 1 (FHL1) acts as a novel interaction partner of PLEKHG2 by the yeast two-hybrid system. Among the isoforms of FHL1 (i.e., FHL1A, FHL1B and FHL1C), FHL1A and FHL1B interacted with PLEKHG2. We found that there was an FHL1-binding region at amino acids 58-150 of PLEKHG2...
October 20, 2016: Journal of Biological Chemistry
Takayuki Koga, Pei-Li Yao, Maryam Goudarzi, Iain A Murray, Gayathri Balandaram, Frank J Gonzalez, Gary H Perdew, Albert J Fornace, Jeffrey M Peters
Alcoholic liver disease is a pathological condition caused by over-consumption of alcohol. Due to the high morbidity and mortality associated with this disease, there remains a need to elucidate the molecular mechanisms underlying its etiology and to develop new treatments. Since peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) modulates ethanol-induced hepatic effects, the present study examined alterations in gene expression that may contribute to this disease. Chronic ethanol treatment causes increased hepatic CYP2B10 expression in Pparβ/δ+/+ mice, but not in Pparβ/δ-/- mice...
October 20, 2016: Journal of Biological Chemistry
Chijun Li, Brandon K Tan, Jinshi Zhao, Ziqiang Guan
Phosphatidylglycerol (PG) makes up 5-20% of the phospholipids of Escherichia coli and is essential for growth in wild-type cells. PG is synthesized from the dephosphorylation of its immediate precursor, phosphatidylglycerol phosphate (PGP) whose synthase in E. coli is PgsA. Using genetic, biochemical and highly sensitive mass spectrometric approaches, we identified an alternative mechanism for PG synthesis in E. coli that is PgsA independent. The reaction of synthesis involves the conversion of phosphatidylethanolamine and glycerol into PG and is catalyzed by ClsB, a phospholipase D-type cardiolipin synthase...
October 19, 2016: Journal of Biological Chemistry
Xiaopeng Xiong, Xin Li, Yang-An Wen, Tianyan Gao
The proper establishment of epithelial polarity allows cells to sense and respond signals that arise from the microenvironment in a spatiotemporally controlled manner. Atypical PKCs (aPKCs) are implicated as key regulators of epithelial polarity. However, the molecular mechanism underlying the negative regulation of aPKCs remains largely unknown. In this study, we demonstrated that PH domain leucine-rich repeat protein phosphatase (PHLPP), a novel family of Ser/Thr protein phosphatases, plays an important role in regulating epithelial polarity by controlling the phosphorylation of both aPKC isoforms...
October 19, 2016: Journal of Biological Chemistry
Meng Wu, Lishann Ingram, Ezequiel J Tolosa, Renzo E Vera, Qianjin Li, Sungjin Kim, Yongjie Ma, Demetri D Spyropoulos, Zanna Beharry, Jiaoti Huang, Martin E Fernandez-Zapico, Houjian Cai
Although the differentiation of oncogenically transformed basal progenitor cells is one of the key steps in prostate tumorigenesis, the mechanisms mediating this cellular process are still largely unknown. Here we demonstrated that an expanded p63+ and CK5+ basal/progenitor cell population, induced by the concomitant activation of oncogenic Kras(G12D) and androgen receptor (AR) signaling, underwent cell differentiation in vivo. The differentiation process led to suppression of the p63 expressing cells with a decreased number of CK5+ basal cells, but an increase of CK8+ luminal tumorigenic cells, and revealed a hierarchal lineage pattern consisting of p63+/CK5+ progenitor, CK5+/CK8+ transitional progenitor, and CK8+ differentiated luminal cells...
October 19, 2016: Journal of Biological Chemistry
Sanae Sekihara, Toshio Shibata, Mai Hyakkendani, Shun-Ichiro Kawabata
We recently reported that transglutaminase (TG) suppresses immune deficiency pathway-controlled antimicrobial peptides (IMD-AMPs), thereby conferring immune tolerance to gut microbes, and that RNAi of the TG gene in flies decreases the lifespan compared with non-TG-RNAi flies. Here, analysis of the bacterial composition of the Drosophila gut by next-generation sequencing revealed that gut microbiota comprising one dominant genus of Acetobacter in non-TG-RNAi flies was shifted to that comprising two dominant genera of Acetobacter and Providencia in TG-RNAi flies...
October 19, 2016: Journal of Biological Chemistry
Shyam Ramachandran, Samantha R Osterhaus, Kalpaj R Parekh, Ashley M Jacobi, Mark A Behlke, Paul B McCray
We previously reported that delivery of a microRNA (miR)-138 mimic or siRNA against SIN3A to cultured cystic fibrosis (CF) (ΔF508/ΔF508) airway epithelia partially restored ΔF508-CFTR mediated cAMP-stimulated Cl-conductance. We hypothesized that dissecting this miR-138/SIN3A regulated gene network would identify individual proteins contributing to the rescue of ΔF508-CFTR function. Among the genes in the network, we rigorously validated candidates using functional CFTR maturation and electrolyte transport assays in polarized airway epithelia...
October 18, 2016: Journal of Biological Chemistry
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