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https://www.readbyqxmd.com/read/27744583/disease-causing-point-mutations-in-metal-binding-domains-of-wilson-disease-protein-decrease-stability-and-increase-structural-dynamics
#1
Ranjeet Kumar, Candan Ariöz, Yaozong Li, Niklas Bosaeus, Sandra Rocha, Pernilla Wittung-Stafshede
After cellular uptake, Copper (Cu) ions are transferred from the chaperone Atox1 to the Wilson disease protein (ATP7B) for incorporation into Cu-dependent enzymes in the secretory pathway. Human ATP7B is a large multi-domain membrane-spanning protein which, in contrast to homologues in other organisms, has six similar cytoplasmic metal-binding domains (MBDs). The reason for multiple MBDs is proposed to be indirect modulation of enzymatic activity and it is thus intriguing that point mutations in MBDs can promote Wilson disease...
October 15, 2016: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
https://www.readbyqxmd.com/read/27666810/endothelial-antioxidant-1-a-key-mediator-of-copper-dependent-wound-healing-in-vivo
#2
Archita Das, Varadarajan Sudhahar, Gin-Fu Chen, Ha Won Kim, Seock-Won Youn, Lydia Finney, Stefan Vogt, Jay Yang, Junghun Kweon, Bayasgalan Surenkhuu, Masuko Ushio-Fukai, Tohru Fukai
Copper (Cu), an essential nutrient, promotes wound healing, however, target of Cu action and underlying mechanisms remain elusive. Cu chaperone Antioxidant-1 (Atox1) in the cytosol supplies Cu to the secretory enzymes such as lysyl oxidase (LOX), while Atox1 in the nucleus functions as a Cu-dependent transcription factor. Using mouse cutaneous wound healing model, here we show that Cu content (by X-ray Fluorescence Microscopy) and nuclear Atox1 are increased after wounding, and that wound healing with and without Cu treatment is impaired in Atox1(-/-) mice...
September 26, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27472369/the-role-of-copper-chaperone-atox1-in-coupling-redox-homeostasis-to-intracellular-copper-distribution
#3
REVIEW
Yuta Hatori, Svetlana Lutsenko
Human antioxidant protein 1 (Atox1) is a small cytosolic protein with an essential role in copper homeostasis. Atox1 functions as a copper carrier facilitating copper transfer to the secretory pathway. This process is required for activation of copper dependent enzymes involved in neurotransmitter biosynthesis, iron efflux, neovascularization, wound healing, and regulation of blood pressure. Recently, new cellular roles for Atox1 have emerged. Changing levels of Atox1 were shown to modulate response to cancer therapies, contribute to inflammatory response, and protect cells against various oxidative stresses...
July 27, 2016: Antioxidants (Basel, Switzerland)
https://www.readbyqxmd.com/read/27401861/transcriptomic-response-of-yeast-cells-to-atx1-deletion-under-different-copper-levels
#4
Ayca Cankorur-Cetinkaya, Serpil Eraslan, Betul Kirdar
BACKGROUND: Iron and copper homeostatic pathways are tightly linked since copper is required as a cofactor for high affinity iron transport. Atx1p plays an important role in the intracellular copper transport as a copper chaperone transferring copper from the transporters to Ccc2p for its subsequent insertion into Fet3p, which is required for high affinity iron transport. RESULTS: In this study, genome-wide transcriptional landscape of ATX1 deletants grown in media either lacking copper or having excess copper was investigated...
2016: BMC Genomics
https://www.readbyqxmd.com/read/27379771/evidence-for-a-role-for-the-putative-drosophila-hgrx1-orthologue-in-copper-homeostasis
#5
Stephen W Mercer, Richard Burke
Glutaredoxins are a family of small molecular weight proteins that have a central role in cellular redox regulation. Human GRX1 (hGRX1) has also been shown to play an integral role in copper homeostasis by regulating the redox activity of the metalated sites of copper chaperones such as ATOX1 and SOD1, and the copper efflux proteins ATP7A and ATP7B. To further elucidate the role of hGRX1 in copper homeostasis, we examined the impact of RNA interference-mediated knockdown of CG6852, a putative Drosophila orthologue of hGRX1...
August 2016: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
https://www.readbyqxmd.com/read/27349676/selenocysteine-containing-analogues-of-atx1-based-peptides-protect-cells-from-copper-ion-toxicity
#6
Michal S Shoshan, Yonat Lehman, Wojciech Goch, Wojciech Bal, Edit Y Tshuva, Norman Metanis
Seleno-substituted model peptides of copper metallochaperone proteins were analyzed for the metal affinity and in vitro anti-oxidative reactivity. An acyclic MTCXXC (X is any amino acid) reference peptide previously analyzed as a potent inhibitor of ROS production underwent substitution of the cysteine residues with selenocysteine to give two singly substituted derivatives C3U and C6U and the doubly substituted analogue C3U/C6U. Presumably due to the softer nature of Se vs. S, all selenocysteine containing peptides demonstrated high affinity to Cu(i), higher than that of the reference peptide, and in the same order of magnitude as that measured for the native protein, Atox1...
August 7, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27305454/oxaliplatin-binding-to-human-copper-chaperone-atox1-and-protein-dimerization
#7
Benny D Belviso, Angela Galliani, Alessia Lasorsa, Valentina Mirabelli, Rocco Caliandro, Fabio Arnesano, Giovanni Natile
Copper trafficking proteins have been implicated in the cellular response to platinum anticancer drugs. We investigated the reaction of the chaperone Atox1 with an activated form of oxaliplatin, the third platinum drug to reach worldwide approval. Unlike cisplatin, which contains monodentate ammines, oxaliplatin contains chelated 1,2-diaminocyclohexane (DACH), which is more resistant to displacement by nucleophiles. In solution, one or two {Pt(DACH)(2+)} moieties bind to the conserved CXXC metal-binding motif of Atox1; in the latter case the two sulfur atoms likely bridging the two platinum units...
July 5, 2016: Inorganic Chemistry
https://www.readbyqxmd.com/read/27222268/tat-atox1-inhibits-streptozotocin-induced-cell-death-in-pancreatic-rinm5f-cells-and-attenuates-diabetes-in-a-mouse-model
#8
Eun Hee Ahn, Dae Won Kim, Min Jea Shin, Eun Ji Ryu, Ji In Yong, Seok Young Chung, Hyun Ju Cha, Sang Jin Kim, Yeon Joo Choi, Duk-Soo Kim, Sung-Woo Cho, Keunwook Lee, Yoon Shin Cho, Hyeok Yil Kwon, Jinseu Park, Won Sik Eum, Soo Young Choi
Antioxidant 1 (ATOX1) functions as an antioxidant against hydrogen peroxide and superoxide, and therefore may play a significant role in many human diseases, including diabetes mellitus (DM). In the present study, we examined the protective effects of Tat-ATOX1 protein on streptozotocin (STZ)-exposed pancreatic insulinoma cells (RINm5F) and in a mouse model of STZ-induced diabetes using western blot analysis, immunofluorescence staining and MTT assay, as well as histological and biochemical analysis. Purified Tat-ATOX1 protein was efficiently transduced into RINm5F cells in a dose- and time-dependent manner...
July 2016: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/27157188/copper-transporters-and-chaperones-ctr1-ctr2-atox1-and-ccs-as-determinants-of-cisplatin-sensitivity
#9
Kristin M Bompiani, Cheng-Yu Tsai, Felix P Achatz, Janika K Liebig, Stephen B Howell
The development of resistance to cisplatin (cDDP) is commonly accompanied by reduced drug uptake or increased efflux. Previous studies in yeast and murine embryonic fibroblasts have reported that the copper (Cu) transporters and chaperones participate in the uptake, efflux, and intracellular distribution of cDDP. However, there is conflicting data from studies in human cells. We used CRISPR-Cas9 genome editing to individually knock out the human copper transporters CTR1 and CTR2 and the copper chaperones ATOX1 and CCS...
September 1, 2016: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/27049121/accumulation-of-copper-in-the-kidney-of-pigs-fed-high-dietary-zinc-is-due-to-metallothionein-expression-with-minor-effects-on-genes-involved-in-copper-metabolism
#10
A Zetzsche, N Schunter, J Zentek, R Pieper
A study was conducted to determine the effect of high dietary zinc (Zn) oxide on trace element accumulation in various organs with special emphasis on the kidney. A total of 40 weaned piglets were allocated into two groups with 16 and 24 piglets each receiving a diet containing normal (NZn; 100mg Zn/kg) or high (HZn; 2,100mg Zn/kg) Zn concentration, respectively. After two weeks, eight piglets from each treatment were killed and organ samples were taken. Eight piglets from the remaining 16 pigs fed HZn diets were changed to NZn diets (CZn)...
May 2016: Journal of Trace Elements in Medicine and Biology
https://www.readbyqxmd.com/read/27031076/rewiring-multidomain-protein-switches-transforming-a-fluorescent-zn-2-sensor-into-a-light-responsive-zn-2-binding-protein
#11
Stijn J A Aper, Maarten Merkx
Protein-based sensors and switches provide attractive tools for the real-time monitoring and control of molecular processes in complex biological environments. Fluorescent sensor proteins have been developed for a wide variety of small molecules, but the construction of genetically encoded light-responsive ligand binding proteins remains mostly unexplored. Here we present a generic approach to reengineer a previously developed FRET-based Zn(2+) sensor into a light-activatable Zn(2+) binding protein using a design strategy based on mutually exclusive domain interactions...
July 15, 2016: ACS Synthetic Biology
https://www.readbyqxmd.com/read/26901629/unbound-position-ii-in-mxcxxc-metallochaperone-model-peptides-impacts-metal-binding-mode-and-reactivity-distinct-similarities-to-whole-proteins
#12
Michal S Shoshan, Noa Dekel, Wojciech Goch, Deborah E Shalev, Tsafi Danieli, Mario Lebendiker, Wojciech Bal, Edit Y Tshuva
The effect of position II in the binding sequence of copper metallochaperones, which varies between Thr and His, was investigated through structural analysis and affinity and oxidation kinetic studies of model peptides. A first Cys-Cu(I)-Cys model obtained for the His peptide at acidic and neutral pH, correlated with higher affinity and more rapid oxidation of its complex; in contrast, the Thr peptide with the Cys-Cu(I)-Met coordination under neutral conditions demonstrated weaker and pH dependent binding. Studies with human antioxidant protein 1 (Atox1) and three of its mutants where S residues were replaced with Ala suggested that (a) the binding affinity is influenced more by the binding sequence than by the protein fold (b) pH may play a role in binding reactivity, and (c) mutating the Met impacted the affinity and oxidation rate more drastically than did mutating one of the Cys, supporting its important role in protein function...
June 2016: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/26879543/neuronal-differentiation-is-associated-with-a-redox-regulated-increase-of-copper-flow-to-the-secretory-pathway
#13
Yuta Hatori, Ye Yan, Katharina Schmidt, Eri Furukawa, Nesrin M Hasan, Nan Yang, Chin-Nung Liu, Shanthini Sockanathan, Svetlana Lutsenko
Brain development requires a fine-tuned copper homoeostasis. Copper deficiency or excess results in severe neuro-pathologies. We demonstrate that upon neuronal differentiation, cellular demand for copper increases, especially within the secretory pathway. Copper flow to this compartment is facilitated through transcriptional and metabolic regulation. Quantitative real-time imaging revealed a gradual change in the oxidation state of cytosolic glutathione upon neuronal differentiation. Transition from a broad range of redox states to a uniformly reducing cytosol facilitates reduction of the copper chaperone Atox1, liberating its metal-binding site...
2016: Nature Communications
https://www.readbyqxmd.com/read/26866891/longitudinal-analytical-approaches-to-genetic-data
#14
Yen-Feng Chiu, Anne E Justice, Phillip E Melton
BACKGROUND: Longitudinal phenotypic data provides a rich potential resource for genetic studies which may allow for greater understanding of variants and their covariates over time. Herein, we review 3 longitudinal analytical approaches from the Genetic Analysis Workshop 19 (GAW19). These contributions investigated both genome-wide association (GWA) and whole genome sequence (WGS) data from odd numbered chromosomes on up to 4 time points for blood pressure-related phenotypes. The statistical models used included generalized estimating equations (GEEs), latent class growth modeling (LCGM), linear mixed-effect (LME), and variance components (VC)...
2016: BMC Genetics
https://www.readbyqxmd.com/read/26797276/copper-binding-triggers-compaction-in-n-terminal-tail-of-human-copper-pump-atp7b
#15
Tanumoy Mondol, Jörgen Åden, Pernilla Wittung-Stafshede
Protein conformational changes are fundamental to biological reactions. For copper ion transport, the multi-domain protein ATP7B in the Golgi network receives copper from the cytoplasmic copper chaperone Atox1 and, with energy from ATP hydrolysis, moves the metal to the lumen for loading of copper-dependent enzymes. Although anticipated, conformational changes involved in ATP7B's functional cycle remain elusive. Using spectroscopic methods we here demonstrate that the four most N-terminal metal-binding domains in ATP7B, upon stoichiometric copper addition, adopt a more compact arrangement which has a higher thermal stability than in the absence of copper...
February 12, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/26794603/novel-elements-of-the-chondrocyte-stress-response-identified-using-an-in-vitro-model-of-mouse-cartilage-degradation
#16
Richard Wilson, Suzanne B Golub, Lynn Rowley, Constanza Angelucci, Yuliya V Karpievitch, John F Bateman, Amanda J Fosang
The destruction of articular cartilage in osteoarthritis involves chondrocyte dysfunction and imbalanced extracellular matrix (ECM) homeostasis. Pro-inflammatory cytokines such as interleukin-1α (IL-1α) contribute to osteoarthritis pathophysiology, but the effects of IL-1α on chondrocytes within their tissue microenvironment have not been fully evaluated. To redress this we used label-free quantitative proteomics to analyze the chondrocyte response to IL-1α within a native cartilage ECM. Mouse femoral heads were cultured with and without IL-1α, and both the tissue proteome and proteins released into the media were analyzed...
March 4, 2016: Journal of Proteome Research
https://www.readbyqxmd.com/read/26784148/atox1-gene-silencing-increases-susceptibility-to-anticancer-therapy-based-on-copper-ionophores-or-chelating-drugs
#17
Vincenza Barresi, Giorgia Spampinato, Nicolò Musso, Angela Trovato Salinaro, Enrico Rizzarelli, Daniele Filippo Condorelli
Copper is a catalytic cofactor required for the normal function of many enzymes involved in fundamental biological processes but highly cytotoxic when in excess. Therefore its homeostasis and distribution is strictly regulated by a network of transporters and intracellular chaperones. ATOX1 (antioxidant protein 1) is a copper chaperone that plays a role in copper homeostasis by binding and transporting cytosolic copper to ATPase proteins in the trans-Golgi network. In the present study the Caco-2 cell line, a colon carcinoma cell line, was used as an in vitro model to evaluate if ATOX1 deficiency could affect sensitivity to experimentally induced copper dyshomeostasis...
March 2016: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/26632864/xas-investigation-of-silver-i-coordination-in-copper-i-biological-binding-sites
#18
Giulia Veronesi, Thomas Gallon, Aurélien Deniaud, Bastien Boff, Christelle Gateau, Colette Lebrun, Claude Vidaud, Françoise Rollin-Genetet, Marie Carrière, Isabelle Kieffer, Elisabeth Mintz, Pascale Delangle, Isabelle Michaud-Soret
Silver(I) is an unphysiological ion that, as the physiological copper(I) ion, shows high binding affinity for thiolate ligands; its toxicity has been proposed to be due to its capability to replace Cu(I) in the thiolate binding sites of proteins involved in copper homeostasis. Nevertheless, the nature of the Ag(I)-thiolate complexes formed within cells is poorly understood, and the details of Ag(I) coordination in such complexes in physiologically relevant conditions are mostly unknown. By making use of X-ray absorption spectroscopy (XAS), we characterized the Ag(I) binding sites in proteins related to copper homeostasis, such as the chaperone Atox1 and metallothioneins (MTs), as well as in bioinspired thiolate Cu(I) chelators mimicking these proteins, in solution and at physiological pH...
December 21, 2015: Inorganic Chemistry
https://www.readbyqxmd.com/read/26587712/inhibition-of-human-copper-trafficking-by-a-small-molecule-significantly-attenuates-cancer-cell-proliferation
#19
Jing Wang, Cheng Luo, Changliang Shan, Qiancheng You, Junyan Lu, Shannon Elf, Yu Zhou, Yi Wen, Jan L Vinkenborg, Jun Fan, Heebum Kang, Ruiting Lin, Dali Han, Yuxin Xie, Jason Karpus, Shijie Chen, Shisheng Ouyang, Chihao Luan, Naixia Zhang, Hong Ding, Maarten Merkx, Hong Liu, Jing Chen, Hualiang Jiang, Chuan He
Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models...
December 2015: Nature Chemistry
https://www.readbyqxmd.com/read/26537407/unresolved-questions-in-human-copper-pump-mechanisms
#20
REVIEW
Pernilla Wittung-Stafshede
Copper (Cu) is an essential transition metal providing activity to key enzymes in the human body. To regulate the levels and avoid toxicity, cells have developed elaborate systems for loading these enzymes with Cu. Most Cu-dependent enzymes obtain the metal from the membrane-bound Cu pumps ATP7A/B in the Golgi network. ATP7A/B receives Cu from the cytoplasmic Cu chaperone Atox1 that acts as the cytoplasmic shuttle between the cell membrane Cu importer, Ctr1 and ATP7A/B. Biological, genetic and structural efforts have provided a tremendous amount of information for how the proteins in this pathway work...
November 2015: Quarterly Reviews of Biophysics
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