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Journal of Biological Chemistry

Jianzhuo Li, Xueqi Fu, Subing Cao, Jing Li, Shu Xing, Dongying Li, Yan Dong, Derrick Landon Cardin, Hee-Won Park, Franck Mauvais-Jarvis, Haitao Zhang
The androgen receptor (AR) is a ligand-activated nuclear receptor that plays a critical role in normal prostate physiology, as well as in the development and progression of prostate cancer. In addition to the classical paradigm in which AR exerts its biological effects in the nucleus by orchestrating the expression of the androgen-regulated transcriptome, there is considerable evidence supporting a rapid, non-genomic activity mediated by membrane-associated AR. Although the genomic action of AR has been studied in depth, the molecular events governing AR transport to the plasma membrane and the downstream AR signaling cascades remain poorly understood...
June 22, 2018: Journal of Biological Chemistry
Amiram Sananes, Itay Cohen, Anat Shahar, Alexandra Hockla, Elena De Vita, Aubry K Miller, Evette S Radisky, Niv Papo
Human tissue kallikrein (KLK) proteases are hormone-like signaling molecules with important functions in cancer pathophysiology. KLK-related peptidase 6 (KLK6), specifically, is highly up-regulated in several types of cancer, where its increased activity promotes cancer invasion and metastasis. This characteristic suggests KLK6 as an attractive target for therapeutic interventions. However, inhibitors that specifically target KLK6 have not yet been reported, possibly because KLK6 shares a high sequence homology and structural similarity with other serine proteases and resists inhibition by many polypeptide inhibitors...
June 22, 2018: Journal of Biological Chemistry
Weili Zheng, Yi Lu, Siyu Tian, Fengge Ma, Yijuan Wei, Shuangshuang Xu, Yong Li
Farnesoid X receptor (FXR) is a member of the family of ligand-activated nuclear receptors. FXR plays critical roles in maintaining many metabolic pathways, including bile acid regulation and glucose and lipid homeostasis, and forms a heterodimeric complex with the retinoid X receptor (RXR). Despite the important roles of the FXR/RXR heterodimerization in human physiology, the molecular basis underlying the FXR/RXR interaction is still uncertain in the absence of a complex structure. Here, we report the heterodimeric structure of FXR and RXR in the presence of an FXR agonist (WAY-362450), RXR agonist (9-cis retinoic acid), and a peptide derived from steroid receptor coactivator (SRC2), revealing both unique and conserved modes for FXR heterodimerization...
June 22, 2018: Journal of Biological Chemistry
Caitlin W Brown, John J Amante, Arthur M Mercurio
Ferroptosis is an iron-dependent form of programmed cell death characterized by the accumulation of lipid-targeting reactive oxygen species that kill cells by damaging their plasma membrane. The lipid-repair enzyme glutathione peroxidase 4 (GPX4) protects against this oxidative damage and enables cells to resist ferroptosis. Recent work has revealed that matrix-detached carcinoma cells can be susceptible to ferroptosis and that they can evade this fate through the signaling properties of the α6β4 integrin, which sustains GPX4 expression...
June 22, 2018: Journal of Biological Chemistry
Yuzuru Taguchi, Li Lu, Cristobal Marrero-Winkens, Hiroki Otaki, Noriyuki Nishida, Hermann M Schatzl
Prions are composed solely of the pathological isoform (PrPSc ) of the normal cellular prion protein (PrPC ). Identification of different PrPSc structures is crucially important for understanding prion biology because the pathogenic properties of prions are hypothesized to be encoded in the structures of PrPSc However, these structures remain yet to be identified, because of the incompatibility of PrPSc with conventional high-resolution structural analysis methods. Previously, we reported that the region between the first and the second alpha-helix (H1~H2) of PrPC might cooperate with the more C-terminal side region for efficient interactions with PrPSc From this starting point, we created a series of PrP variants with two cysteine substitutions (C;C-PrP) forming a disulfide crosslink between H1~H2 and the distal region of the third helix (Ctrm)...
June 22, 2018: Journal of Biological Chemistry
Lucie Colineau, Ulrike Lambertz, Oriol Fornes, Wyeth W Wasserman, Neil E Reiner
Leishmania species are intracellular protozoan pathogens that have evolved to successfully infect and deactivate host macrophages. How this deactivation is brought about is not completely understood. Recently, microRNAs (miRNAs) have emerged as ubiquitous regulators of macrophage gene expression that contribute to shaping the immune responses to intracellular pathogens. Conversely, several pathogens have evolved the ability to exploit host miRNA expression in order to manipulate host cell phenotype. However, very little is known about the mechanisms used by intracellular pathogens to drive changes in host cell miRNA abundance...
June 22, 2018: Journal of Biological Chemistry
Eli Fernández-de Gortari, L Michel Espinoza-Fonseca
Sarcoplasmic reticulum Ca2+ -ATPase (SERCA) is critical for cardiac Ca2+ transport. Reversal of phospholamban (PLB)-mediated SERCA inhibition by saturating Ca2+ conditions operates as a physiological rheostat to reactivate SERCA function in the absence of PLB phosphorylation. Here, we performed extensive atomistic molecular dynamics simulations to probe the structural mechanism of this process. Simulation of the inhibitory complex at super-physiological Ca2+ concentrations ([Ca2+ ] = 10 mM) revealed that Ca2+ ions interact primarily with SERCA and the lipid headgroups, but not with PLB's cytosolic domain or the cytosolic side of the SERCA-PLB interface...
June 22, 2018: Journal of Biological Chemistry
Eunice C Chan, Chunguang Ren, Zhihui Xie, Joseph A Jude, Tolga Barker, Cynthia A Koziol-White, Michelle Ma, Reynold A Panettieri, Dianqing Wu, Helene F Rosenberg, Kirk M Druey
Neutrophils are white blood cells that are mobilized to damaged tissues and to sites of pathogen invasion, providing the first line of host defense. Chemokines displayed on the surface of blood vessels promote migration of neutrophils to these sites, and tissue-and pathogen derived chemoattractant signals, including N-formylmethionyl-leucyl-phenylalanine (fMLP) elicit further migration to sites of infection. Although nearly all chemoattractant receptors use heterotrimeric G proteins to transmit signals, many of the mechanisms lying downstream of chemoattractant receptors that either promote or limit neutrophil motility are incompletely defined...
June 21, 2018: Journal of Biological Chemistry
Alexander N Scherer, Neha S Anand, Anthony J Koleske
The actin-binding protein cortactin promotes the formation and maintenance of actin-rich structures, including lamellipodial protrusions in fibroblasts and neuronal dendritic spines. Cortactin cellular functions have been attributed to its activation of the Arp2/3 complex, which stimulates actin branch nucleation, and to its recruitment of Rho family GTPase regulators. Cortactin also binds actin filaments and significantly slows filament depolymerization, but the mechanism by which it does so, and the relationship between actin binding and stabilization, is unclear...
June 21, 2018: Journal of Biological Chemistry
Yvan Jamilloux, Brice Lagrange, Antonia Di MIcco, Emilie Bourdonnay, Angélina Provost, Rémy Tallant, Thomas Henry, Fabio Martinon
The inflammasome is a major component of the innate immune system, and its main function is to activate caspase-1, a cysteine protease that promotes inflammation by inducing interleukin-1β (IL-1β) maturation and release into the extracellular milieu. To prevent uncontrolled inflammation, this complex is highly regulated. Once it is assembled, the inflammasome is insoluble, which has long precluded the analysis of its interactions with other proteins. Here, we used the proximity-dependent biotinylation assay (BioID) to identify proteins associated with caspase-1 during inflammasome activation...
June 21, 2018: Journal of Biological Chemistry
Xijun Liu, Ruyi Xue, Caiting Yang, Jianxin Gu, She Chen, Si Zhang
The liver is the main site of estrogen metabolism, and liver disease is usually associated with an abnormal estrogen status. However, little is known about the mechanism underlying this connection. Here, we investigated the effects of bile acid (BA)-activated Farnesoid X receptor (FXR) on the metabolism of 17β-estradiol (E2) during blockage of bile flow (cholestasis). Correlations between BA levels and E2 concentrations were established in patients with cholestasis, and hepatic expression profiles of key genes involved in estrogen metabolism were investigated in both WT and FXR-/- mice...
June 21, 2018: Journal of Biological Chemistry
Danwei Yu, Xiaohui Ding, Zixian Liu, Xiyuan Wu, Yuanmei Zhu, Huamian Wei, Huihui Chong, Sheng Cui, Yuxian He
Host cell infection with HIV-1 requires fusion of viral and cell membranes. Sifuvirtide (SFT) is a peptide-based HIV-1 fusion inhibitor approved for phase III clinical trials in China. Here, we focused on characterizing HIV-1 variants highly resistant to SFT to gain insight into the molecular resistance mechanism. Three primary substitutions (V38A, A47I, and Q52R) located at the inhibitor-binding site of HIV-1's envelope protein (Env) and one secondary substitution (N126K) located at the C-terminal heptad repeat region of the viral protein gp41, which is part of the envelope, conferred high SFT resistance and cross-resistance to the anti-HIV-1 drug T20 and the template peptide C34...
June 21, 2018: Journal of Biological Chemistry
Jeremy S Morris, Ryan A Groves, Jillian M Hagel, Peter J Facchini
Phenylalkylamines, such as the plant compounds ephedrine and pseudoephedrine and the animal neurotransmitters dopamine and adrenaline, compose a large class of natural and synthetic molecules with important physiological functions and pharmaceutically valuable bioactivities. The final steps of ephedrine and pseudoephedrine biosynthesis in members of the plant genus Ephedra involve N -methylation of norephedrine and norpseudoephedrine, respectively. Here, using a plant transcriptome screen, we report the isolation and characterization of an N -methyltransferase (NMT) from Ephedra sinica able to catalyze the formation of (pseudo)ephedrine and other naturally occurring phenylalkylamines, including N -methylcathinone and N -methyl(pseudo)ephedrine...
June 21, 2018: Journal of Biological Chemistry
Liang-Yu Chen, Martin Lotz, Robert A Terkeltaub, Ru Liu-Bryan
Certain dysregulated chondrocyte metabolic adaptive responses such as decreased activity of the master regulator of energy metabolism AMP-activated protein kinase (AMPK), promote osteoarthritis (OA). Metabolism intersects with epigenetic and transcriptional responses. Hence, we studied chondrocyte ATP-citrate lyase (ACLY), which generates acetyl-CoA from mitochondrial-derived citrate, and modulates acetylation of histones and transcription factors.            We assessed ACLY in normal and OA human knee chondrocytes and cartilages by Western blot and immunohistochemistry, and quantified acetyl-CoA fluorometrically...
June 21, 2018: Journal of Biological Chemistry
Kondapalli Mrudula Spurthi, Mohsen Sarikhani, Sneha Mishra, Perumal Arumugam Desingu, Shikha Yadav, Swathi Rao, Sangeeta Maity, Ankit Kumar Tamta, Shweta Kumar, Shamik Majumdar, Aditi Jain, Aishwarya Raghuraman, Danish Khan, Ishwar Singh, Rosa J Samuel, Subbaraya G Ramachandra, Dipankar Nandi, Nagalingam R Sundaresan
Toll-like receptors (TLRs) are a family of pattern-recognition receptors involved in innate immunity. Previous studies have shown that TLR2 inhibition protects the heart from acute stress, including myocardial infarction and doxorubicin-induced cardiotoxicity in animal models. However, the role of TLR2 in the development of aging-associated heart failure is not known. In this work, we studied aging-associated changes in structure and function of TLR2- deficient mice hearts. Whereas young TLR2-KO mice did not develop marked cardiac dysfunction, 8- and 12-months-old TLR2-KO mice exhibited spontaneous adverse cardiac remodeling and cardiac dysfunction in an age-dependent manner...
June 21, 2018: Journal of Biological Chemistry
Seda Seren, Maha Rashed Abouzaid, Claudia Eulenberg-Gustavus, Josefine Hirschfeld, Hala Soliman, Uwe Jerke, Koffi N'Guessan, Sandrine Dallet-Choisy, Adam Lesner, Conni Lauritzen, Beate Schacher, Peter Eickholz, Nikoletta Nagy, Marta Szell, Cécile Croix, Marie-Claude Viaud-Massuard, Abdullah Al Farraj Aldosari, Shivanna Ragunatha, Mostafa Ibrahim Mostafa, Francesca Giampieri, Maurizio Battino, Hélène Cornillier, Gérard Lorette, Jean-Louis Stephan, Cyril Goizet, John Pedersen, Francis Gauthier, Dieter E Jenne, Sylvain Marchand-Adam, Iain L Chapple, Ralph Kettritz, Brice Korkmaz
Membrane-bound proteinase 3 (PR3m) is the main target antigen of anti-neutrophil cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis (GPA). Binding of ANCA to PR3m triggers neutrophil activation with the secretion of enzymatically active  proteases, thereby contributing to vascular damage. PR3 and related proteases are activated from proforms by the lysosomal cysteine protease cathepsin C (CatC) during neutrophil maturation. We hypothesized that pharmacological inhibition of CatC provides an effective measure to reduce PR3m and has therefore implications as a novel therapeutic approach in GPA...
June 20, 2018: Journal of Biological Chemistry
Kateřina Melková, Vojtěch Zapletal, Séverine Jansen, Erik Nomilner, Milan Zachrdla, Jozef Hritz, Jiří Nováček, Markus Zweckstetter, Malene R Jensen, Martin Blackledge, Lukas Zidek
Microtubule-associated protein 2c (MAP2c)1 is a 49-kDa intrinsically disordered protein regulating the dynamics of microtubules in developing neurons. MAP2c differs from its sequence homologue Tau in the pattern and kinetics of phosphorylation by cAMP-dependent protein kinase (PKA). Moreover, the mechanisms through which MAP2c interacts with its binding partners and the conformational changes and dynamics associated with these interactions remain unclear. Here, we used NMR relaxation and paramagnetic relaxation enhancement techniques to determine the dynamics and long-range interactions within MAP2c...
June 20, 2018: Journal of Biological Chemistry
Pingzheng Zhou, Maya M Polovitskaya, Thomas J Jentsch
Volume-regulated anion channels (VRACs) are crucial for cell volume regulation and have various roles in physiology and pathology. VRACs were recently discovered to be formed by heteromers of LRRC8 (leucine-rich repeat-containing 8) proteins. However, the structural determinants of VRAC permeation and gating remain largely unknown. We show here that the short stretch preceding the first LRRC8 transmembrane domain determines VRAC conductance, ion permeability and inactivation gating. Substituted cysteine accessibility studies revealed that several of the first 15 LRRC8 residues are functionally important and exposed to a hydrophilic environment...
June 20, 2018: Journal of Biological Chemistry
Petra Skotnicová, Roman Sobotka, Mark Shepherd, Jan Hájek, Pavel Hrouzek, Martin Tichý
Protoporphyrinogen IX oxidase (PPO), the last enzyme that is common to both chlorophyll and heme biosynthesis pathways, catalyzes the oxidation of protoporphyrinogen IX to protoporphyrin IX. PPO has several isoforms, including the oxygen-dependent HemY and an oxygen-independent enzyme, HemG. However, most cyanobacteria encode HemJ, the least characterized PPO form. We have characterized HemJ from the cyanobacterium Synechocystis sp. PCC 6803 ( Synechocystis 6803) as a bona fide PPO; HemJ down-regulation resulted in accumulation of tetrapyrrole precursors and in the depletion of chlorophyll precursors...
June 20, 2018: Journal of Biological Chemistry
Saleha Patel, Alice M Barkell, Deepti Gupta, Sarah L Strong, Shaun Bruton, Frederick W Muskett, Philip W Addis, Philip S Renshaw, Patrick M Slocombe, Carl Doyle, Alison Clargo, Richard J Taylor, Christine E Prosser, Alistair J Henry, Martyn K Robinson, Lorna C Waters, Gill Holdsworth, Mark David Carr
Dickkopf (Dkk) family proteins are important regulators of Wnt signalling pathways, which play key roles in many essential biological processes. Here we report the first detailed structural and dynamics study of a full-length mature Dkk protein (Dkk4, residues 19-224), including determination of the first atomic resolution structure for the N-terminal cysteine-rich domain (CRD1) conserved among Dkk proteins. We discovered that CRD1 has significant structural homology to the Dkk C-terminal cysteine-rich domain (CRD2), pointing to multiple gene duplication events during Dkk family evolution...
June 20, 2018: Journal of Biological Chemistry
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