scholarly journals Regulation of murine copper homeostasis by members of the COMMD protein family

2020 ◽  
Vol 14 (1) ◽  
pp. dmm045963
Author(s):  
Amika Singla ◽  
Qing Chen ◽  
Kohei Suzuki ◽  
Jie Song ◽  
Alina Fedoseienko ◽  
...  
Keyword(s):  
Copper Homeostasis ◽  
Copper Accumulation ◽  
Copper Transporter ◽  
Copper Excretion ◽  
Copper Absorption ◽  
Hepatic Copper ◽  
High Copper ◽  
Molecular Machinery ◽  
And Function

ABSTRACTCopper is an essential transition metal for all eukaryotes. In mammals, intestinal copper absorption is mediated by the ATP7A copper transporter, whereas copper excretion occurs predominantly through the biliary route and is mediated by the paralog ATP7B. Both transporters have been shown to be recycled actively between the endosomal network and the plasma membrane by a molecular machinery known as the COMMD/CCDC22/CCDC93 or CCC complex. In fact, mutations in COMMD1 can lead to impaired biliary copper excretion and liver pathology in dogs and in mice with liver-specific Commd1 deficiency, recapitulating aspects of this phenotype. Nonetheless, the role of the CCC complex in intestinal copper absorption in vivo has not been studied, and the potential redundancy of various COMMD family members has not been tested. In this study, we examined copper homeostasis in enterocyte-specific and hepatocyte-specific COMMD gene-deficient mice. We found that, in contrast to effects in cell lines in culture, COMMD protein deficiency induced minimal changes in ATP7A in enterocytes and did not lead to altered copper levels under low- or high-copper diets, suggesting that regulation of ATP7A in enterocytes is not of physiological consequence. By contrast, deficiency of any of three COMMD genes (Commd1, Commd6 or Commd9) resulted in hepatic copper accumulation under high-copper diets. We found that each of these deficiencies caused destabilization of the entire CCC complex and suggest that this might explain their shared phenotype. Overall, we conclude that the CCC complex plays an important role in ATP7B endosomal recycling and function.

scholarly journals Pharmacoproteomics pinpoints HSP70 interaction for correction of the most frequent Wilson disease-causing mutant of ATP7B

2020 ◽  
Vol 117 (51) ◽  
pp. 32453-32463
Author(s):  
Mafalda Concilli ◽  
Raffaella Petruzzelli ◽  
Silvia Parisi ◽  
Federico Catalano ◽  
Francesco Sirci ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Wilson Disease ◽  
Therapeutic Strategy ◽  
Copper Accumulation ◽  
Loss Of Function ◽  
Copper Transporter ◽  
Hepatic Copper ◽  
Hepatic Cells ◽  
Approved Drugs ◽  
And Function

Pathogenic mutations in the copper transporterATP7Bhave been hypothesized to affect its protein interaction landscape contributing to loss of function and, thereby, to hepatic copper toxicosis in Wilson disease. Although targeting mutant interactomes was proposed as a therapeutic strategy, druggable interactors for rescue of ATP7B mutants remain elusive. Using proteomics, we found that the frequent H1069Q substitution promotes ATP7B interaction with HSP70, thus accelerating endoplasmic reticulum (ER) degradation of the mutant protein and consequent copper accumulation in hepatic cells. This prompted us to use an HSP70 inhibitor as bait in a bioinformatics search for structurally similar Food and Drug Administration-approved drugs. Among the hits, domperidone emerged as an effective corrector that recovered trafficking and function of ATP7B-H1069Q by impairing its exposure to the HSP70 proteostatic network. Our findings suggest that HSP70-mediated degradation can be safely targeted with domperidone to rescue ER-retained ATP7B mutants and, hence, to counter the onset of Wilson disease.

scholarly journals Essential Roles in Development and Pigmentation for the Drosophila Copper Transporter DmATP7

2006 ◽  
Vol 17 (1) ◽  
pp. 475-484 ◽  
Author(s):  
Melanie Norgate ◽  
Esther Lee ◽  
Adam Southon ◽  
Ashley Farlow ◽  
Philip Batterham ◽  
...  
Keyword(s):  
Copper Homeostasis ◽  
Cellular Level ◽  
Loss Of Function ◽  
Neuronal Function ◽  
Copper Transporter ◽  
Disease Phenotypes ◽  
In Vivo Analysis ◽  
Cellular Copper ◽  
P Type

Defects in the mammalian Menkes and Wilson copper transporting P-type ATPases cause severe copper homeostasis disease phenotypes in humans. Here, we find that DmATP7, the sole Drosophila orthologue of the Menkes and Wilson genes, is vital for uptake of copper in vivo. Analysis of a DmATP7 loss-of-function allele shows that DmATP7 is essential in embryogenesis, early larval development, and adult pigmentation and is probably required for copper uptake from the diet. These phenotypes are analogous to those caused by mutation in the mouse and human Menkes genes, suggesting that like Menkes, DmATP7 plays at least two roles at the cellular level: delivering copper to cuproenzymes required for pigmentation and neuronal function and removing excess cellular copper via facilitated efflux. DmATP7 displays a dynamic and unexpected expression pattern in the developing embryo, implying novel functions for this copper pump and the lethality observed in DmATP7 mutant flies is the earliest seen for any copper homeostasis gene.

Excessive Hepatic Copper Accumulation in Jaundiced Rats Fed a High-Copper Diet

2002 ◽  
Vol 88 (3) ◽  
pp. 255-270
Author(s):  
A. C. Beynen ◽  
S. Yu ◽  
R. Van Der Meer
Keyword(s):  
Copper Accumulation ◽  
Hepatic Copper ◽  
High Copper

Hepatocyte-specific localization and copper-dependent trafficking of the Wilson’s disease protein in the liver

1999 ◽  
Vol 276 (3) ◽  
pp. G639-G646 ◽  
Author(s):  
Mark Schaefer ◽  
Robin G. Hopkins ◽  
Mark L. Failla ◽  
Jonathan D. Gitlin
Keyword(s):  
Wilson’S Disease ◽  
Neuronal Degeneration ◽  
Copper Metabolism ◽  
Wilson's Disease ◽  
Polyclonal Antiserum ◽  
Copper Excretion ◽  
Hepatic Expression ◽  
Hepatic Copper ◽  
Disease Protein

Wilson’s disease is an inherited disorder of copper metabolism characterized by hepatic cirrhosis and neuronal degeneration. In this current study, a polyclonal antiserum specific for the Wilson’s disease ATPase was used to examine the hepatic expression of this protein. Immunoblot analysis of lysates from human and rat liver detected a single 165-kDa protein, which by immunofluorescence was present only in hepatocytes and localized predominantly to the trans-Golgi network and exclusively in this compartment under low hepatic copper concentrations. Although hepatic copper concentration had no effect on the steady-state levels of the Wilson’s disease protein, copper administration in vivo resulted in redistribution of this protein to a cytoplasmic vesicular compartment localized toward the hepatocyte canalicular membrane. The relative abundance of the Wilson’s disease protein in the liver was found to be greatest in the fetus before the onset of biliary copper excretion. Taken together, these studies reveal a novel posttranslational mechanism of copper homeostasis in vivo consistent with the proposed function of the Wilson’s disease protein in holoceruloplasmin biosynthesis and biliary copper excretion and of relevance to the broad clinical heterogeneity observed in this disease.

scholarly journals Copper binding by a unique family of metalloproteins is dependent on kynurenine formation

2021 ◽  
Vol 118 (23) ◽  
pp. e2100680118
Author(s):  
Anastasia C. Manesis ◽  
Richard J. Jodts ◽  
Brian M. Hoffman ◽  
Amy C. Rosenzweig
Keyword(s):  
Biochemical Characterization ◽  
Protein A ◽  
Copper Ion ◽  
Copper Homeostasis ◽  
Metabolic Enzyme ◽  
Copper Binding ◽  
Methane Oxidizing Bacteria ◽  
And Function

Some methane-oxidizing bacteria use the ribosomally synthesized, posttranslationally modified natural product methanobactin (Mbn) to acquire copper for their primary metabolic enzyme, particulate methane monooxygenase. The operons encoding the machinery to biosynthesize and transport Mbns typically include genes for two proteins, MbnH and MbnP, which are also found as a pair in other genomic contexts related to copper homeostasis. While the MbnH protein, a member of the bacterial diheme cytochrome c peroxidase (bCcP)/MauG superfamily, has been characterized, the structure and function of MbnP, the relationship between the two proteins, and their role in copper homeostasis remain unclear. Biochemical characterization of MbnP from the methanotroph Methylosinus trichosporium OB3b now reveals that MbnP binds a single copper ion, present in the +1 oxidation state, with high affinity. Copper binding to MbnP in vivo is dependent on oxidation of the first tryptophan in a conserved WxW motif to a kynurenine, a transformation that occurs through an interaction of MbnH with MbnP. The 2.04-Å-resolution crystal structure of MbnP reveals a unique fold and an unusual copper-binding site involving a histidine, a methionine, a solvent ligand, and the kynurenine. Although the kynurenine residue may not serve as a CuI primary-sphere ligand, being positioned ∼2.9 Å away from the CuI ion, its presence is required for copper binding. Genomic neighborhood analysis indicates that MbnP proteins, and by extension kynurenine-containing copper sites, are widespread and may play diverse roles in microbial copper homeostasis.

scholarly journals Evaluation of a commercially available molybdate formulation and zinc oxide boluses in preventing hepatic copper accumulation and thus enzootic icterus in sheep

2001 ◽  
Vol 72 (4) ◽  
Author(s):  
C.J. Botha ◽  
A.S. Shakespeare ◽  
R. Gehring ◽  
D. Van der Merwe
Keyword(s):  
Zinc Oxide ◽  
Copper Concentration ◽  
Histopathological Examination ◽  
Copper Accumulation ◽  
Copper Excretion ◽  
Hepatic Copper ◽  
Liver Copper ◽  
Urinary Copper ◽  
Plasma Copper ◽  
Urinary Copper Excretion

The efficacy of a molybdate formulation and a zinc oxide bolus as prophylactic agents for enzootic icterus was evaluated in sheep. Before copper loading, liver biopsies were performed on 12 male, 6-month-old, Mutton Merino sheep to determine hepatic copper (Cu) and zinc (Zn) concentrations. The animals were restrictively randomised according to liver copper concentrations to 3 treatment groups (n = 4) to achieve similar mean liver copper concentrations per group. All sheep received 4 m /kg of a 0.5 %aqueous solution of CuSO4·5H2O intraruminally 7 days per week for 10 weeks. On Day 0 the sheep in the Mo-group were injected subcutaneously with 42 mg molybdenum (Mo) contained in a commercial molybdate formulation. The animals in the Zn-group each received a zinc oxide bolus, containing 43 g zinc oxide, via a rumen cannula. Treatment was repeated on Day 42. Four animals served as untreated controls. Urinary copper excretion, plasma copper concentration, haematocrit and glutamate dehydrogenase (GLDH) activity were determined throughout the trial. The animals were sacrificed after 10 weeks and liver samples were submitted for histopathological examination. Liver and kidney copper and zinc concentrations were determined. Neither the molybdate treatment nor the zinc oxide boluses prevented hepatic copper accumulation. The urinary copper excretion, plasma copper concentration, haematocrit and GLDH activity were not significantly different (P > 0.05) from the controls.

scholarly journals Achieving functional neuronal dendrite structure through sequential stochastic growth and retraction

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
André Ferreira Castro ◽  
Lothar Baltruschat ◽  
Tomke Stürner ◽  
Amirhoushang Bahrami ◽  
Peter Jedlicka ◽  
...  
Keyword(s):  
Time Lapse ◽  
Membrane Curvature ◽  
Larval Body ◽  
Stochastic Growth ◽  
Molecular Machinery ◽  
Neuronal Dendrite ◽  
And Function ◽  
Dendritic Branches ◽  
Time Lapse Imaging

Class I ventral posterior dendritic arborisation (c1vpda) proprioceptive sensory neurons respond to contractions in the Drosophila larval body wall during crawling. Their dendritic branches run along the direction of contraction, possibly a functional requirement to maximise membrane curvature during crawling contractions. Although the molecular machinery of dendritic patterning in c1vpda has been extensively studied, the process leading to the precise elaboration of their comb-like shapes remains elusive. Here, to link dendrite shape with its proprioceptive role, we performed long-term, non-invasive, in vivo time-lapse imaging of c1vpda embryonic and larval morphogenesis to reveal a sequence of differentiation stages. We combined computer models and dendritic branch dynamics tracking to propose that distinct sequential phases of stochastic growth and retraction achieve efficient dendritic trees both in terms of wire and function. Our study shows how dendrite growth balances structure–function requirements, shedding new light on general principles of self-organisation in functionally specialised dendrites.

scholarly journals COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A

2015 ◽  
Vol 26 (1) ◽  
pp. 91-103 ◽  
Author(s):  
Christine A. Phillips-Krawczak ◽  
Amika Singla ◽  
Petro Starokadomskyy ◽  
Zhihui Deng ◽  
Douglas G. Osborne ◽  
...  
Keyword(s):  
Copper Homeostasis ◽  
Mechanistic Explanation ◽  
Copper Accumulation ◽  
Endosomal Trafficking ◽  
Copper Transporter ◽  
Early Endosomes ◽  
Evolutionarily Conserved ◽  
Carboxyl Terminal ◽  
Intracellular Copper

COMMD1 deficiency results in defective copper homeostasis, but the mechanism for this has remained elusive. Here we report that COMMD1 is directly linked to early endosomes through its interaction with a protein complex containing CCDC22, CCDC93, and C16orf62. This COMMD/CCDC22/CCDC93 (CCC) complex interacts with the multisubunit WASH complex, an evolutionarily conserved system, which is required for endosomal deposition of F-actin and cargo trafficking in conjunction with the retromer. Interactions between the WASH complex subunit FAM21, and the carboxyl-terminal ends of CCDC22 and CCDC93 are responsible for CCC complex recruitment to endosomes. We show that depletion of CCC complex components leads to lack of copper-dependent movement of the copper transporter ATP7A from endosomes, resulting in intracellular copper accumulation and modest alterations in copper homeostasis in humans with CCDC22 mutations. This work provides a mechanistic explanation for the role of COMMD1 in copper homeostasis and uncovers additional genes involved in the regulation of copper transporter recycling.

scholarly journals Crossroads between membrane trafficking machinery and copper homeostasis in the nerve system

Open Biology ◽  
2021 ◽  
Vol 11 (12) ◽  
Author(s):  
Meng-Hsuan Wen ◽  
Xihong Xie ◽  
Pei-San Huang ◽  
Karen Yang ◽  
Tai-Yen Chen
Keyword(s):  
Systematic Review ◽  
Membrane Trafficking ◽  
Current Knowledge ◽  
Copper Homeostasis ◽  
Copper Transporter ◽  
Membrane Compartments ◽  
Copper Dyshomeostasis ◽  
Nerve System ◽  
Intracellular Copper

Imbalanced copper homeostasis and perturbation of membrane trafficking are two common symptoms that have been associated with the pathogenesis of neurodegenerative and neurodevelopmental diseases. Accumulating evidence from biophysical, cellular and in vivo studies suggest that membrane trafficking orchestrates both copper homeostasis and neural functions—however, a systematic review of how copper homeostasis and membrane trafficking interplays in neurons remains lacking. Here, we summarize current knowledge of the general trafficking itineraries for copper transporters and highlight several critical membrane trafficking regulators in maintaining copper homeostasis. We discuss how membrane trafficking regulators may alter copper transporter distribution in different membrane compartments to regulate intracellular copper homeostasis. Using Parkinson's disease and MEDNIK as examples, we further elaborate how misregulated trafficking regulators may interplay parallelly or synergistically with copper dyshomeostasis in devastating pathogenesis in neurodegenerative diseases. Finally, we explore multiple unsolved questions and highlight the existing challenges to understand how copper homeostasis is modulated through membrane trafficking.

scholarly journals Deletion of hepatic Ctr1 reveals its function in copper acquisition and compensatory mechanisms for copper homeostasis

2009 ◽  
Vol 296 (2) ◽  
pp. G356-G364 ◽  
Author(s):  
Heejeong Kim ◽  
Hwa-Young Son ◽  
Sarah M. Bailey ◽  
Jaekwon Lee
Keyword(s):  
Critical Role ◽  
Copper Metabolism ◽  
Copper Homeostasis ◽  
Normal Growth ◽  
Copper Uptake ◽  
Compensatory Mechanisms ◽  
Copper Transporter ◽  
Hepatic Copper ◽  
Urinary Copper ◽  
Copper Transporter 1

Copper is a vital trace element required for normal growth and development of many organisms. To determine the roles for copper transporter 1 (Ctr1) in hepatic copper metabolism and the contribution of the liver to systemic copper homeostasis, we have generated and characterized mice in which Ctr1 is deleted specifically in the liver. These mice express less than 10% residual Ctr1 protein in the liver and exhibit a small but significant growth retardation, which disappears with age. Hepatic copper concentrations and the activities of copper-requiring enzymes are reduced; however, mild copper deficiency relative to Ctr1 protein deficit indicates compensatory mechanisms for copper metabolism. Copper concentrations of other organs did not alter despite the defect in hepatic copper uptake. Whereas biliary copper excretion is reduced, urinary copper concentration in these mice is higher than that of control mice. Our data indicate that Ctr1 plays a critical role in copper acquisition in the liver, and, when Ctr1 expression is compromised, compensatory mechanisms facilitate copper uptake and/or retention in the liver and excretion of copper via urine.

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