In silico modeling of the Menkes copper-translocating P-type ATPase 3rd metal binding domain predicts that phosphorylation regulates copper-binding

Veldhuis, Nicholas A.; Kuiper, Michael J.; Dobson, Renwick C. J.; Pearson, Richard B.; Camakaris, James

doi:10.1007/s10534-011-9410-0

Cited by 6 publications

(7 citation statements)

References 44 publications

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“…In both experiments, correct trafficking to the plasma membrane and delivery to the basolateral membrane (in polarized MDCKs) upon copper stimulation was observed. These results are in line with previous observations that the phosphorylation site ATP7A:pT327 is not involved in aberrant trafficking of ATP7A ( Veldhuis et al, 2009 ), but is rather predicted to stabilize a conformational change in ATP7A, exposing the CxxC copper-binding region of MBD3, which might affect catalytic activity of ATP7A ( Veldhuis et al, 2011 ). This might indicate that catalytic activity, rather than aberrant trafficking of ATP7A, is responsible for the observed decrease in hepatic copper levels in Labrador retrievers.…”

Section: Discussionsupporting

confidence: 92%

“…MBD3 is located in the cytoplasm and has the ability to receive copper from the Atox1 chaperone ( Strausak et al, 2003 ). MBD3 of ATP7A is only metallated in elevated copper conditions ( Banci et al, 2010 ) and is thought to be an important domain for regulating ATP7A activity via cell-signalling pathways ( Veldhuis et al, 2011 ). It has been shown that ATP7A:p.T327 is an important phosphorylation site of ATP7A ( Veldhuis et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

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The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders

Fieten

Gill²,

Martin³

et al. 2016

Disease Models &Amp; Mechanisms

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The deleterious effects of a disrupted copper metabolism are illustrated by hereditary diseases caused by mutations in the genes coding for the copper transporters ATP7A and ATP7B. Menkes disease, involving ATP7A, is a fatal neurodegenerative disorder of copper deficiency. Mutations in ATP7B lead to Wilson disease, which is characterized by a predominantly hepatic copper accumulation. The low incidence and the phenotypic variability of human copper toxicosis hamper identification of causal genes or modifier genes involved in the disease pathogenesis. The Labrador retriever was recently characterized as a new canine model for copper toxicosis. Purebred dogs have reduced genetic variability, which facilitates identification of genes involved in complex heritable traits that might influence phenotype in both humans and dogs. We performed a genome-wide association study in 235 Labrador retrievers and identified two chromosome regions containing ATP7A and ATP7B that were associated with variation in hepatic copper levels. DNA sequence analysis identified missense mutations in each gene. The amino acid substitution ATP7B:p.Arg1453Gln was associated with copper accumulation, whereas the amino acid substitution ATP7A:p.Thr327Ile partly protected against copper accumulation. Confocal microscopy indicated that aberrant copper metabolism upon expression of the ATP7B variant occurred because of mis-localization of the protein in the endoplasmic reticulum. Dermal fibroblasts derived from ATP7A:p.Thr327Ile dogs showed copper accumulation and delayed excretion. We identified the Labrador retriever as the first natural, non-rodent model for ATP7B-associated copper toxicosis. Attenuation of copper accumulation by the ATP7A mutation sheds an interesting light on the interplay of copper transporters in body copper homeostasis and warrants a thorough investigation of ATP7A as a modifier gene in copper-metabolism disorders. The identification of two new functional variants in ATP7A and ATP7B contributes to the biological understanding of protein function, with relevance for future development of therapy.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders

Fieten

Gill²,

Martin³

et al. 2016

Disease Models &Amp; Mechanisms

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“…58 Recently, Veldhuis et al suggested, using MD simulations, that S339, which is in a loop facing the copper binding site, may facilitate the copper transfer process by exposing the CxxC copper binding region of MBD3 while copper-induced phosphorylation of T327 would stabilize this change in conformation. 59 In our simulations, Cys1 in Mnk3 apo is indeed largely solvent-exposed while Cys2 is completely buried, but the result is an exposed CxxC motif in Mnk3 holo (high g H in Table 4). The possibility of a low level of exposure of Cys2 to the solvent is supported by fluorescence labeling experiments by Yatsunyk et al on the MBDs of the related Wilson protein, showing that the cysteines of MBD3 were the least solventexposed.…”

Section: ■ Discussion and Conclusionmentioning

confidence: 63%

Dynamics and Stability of the Metal Binding Domains of the Menkes ATPase and Their Interaction with Metallochaperone HAH1

Arumugam

Crouzy

2012

Biochemistry

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Human copper-ATPases ATP7A and ATP7B are essential for intracellular copper homeostasis. The main roles of the Menkes protein, ATP7A, are the delivery of copper to the secretory pathway and the export of excess copper from the enterocytes. The N-terminal domain of membrane protein ATP7A consists of six repetitive sequences of 60-70 amino acids (Mnk1-Mnk6) that fold into individual metal binding domains (MBDs) and bind a single copper ion in the reduced Cu(I) form via two cysteine residues. The structure of each individual MBD is known from nuclear magnetic resonance experiments. Here, we were interested in the stability and dynamics of each isolated MBD in their apo and holo forms and their interactions with the soluble metallochaperone HAH1 that delivers copper to ATP7A. Using molecular dynamics simulations of the MBDs under different conditions, we show that some MBDs (Mnk1 and Mnk5) present large root-mean-square deviations from initial structures or large root-mean-square fluctuations, and great care has to be taken in setting up the simulations. We propose that the first MBD, Mnk1, probably important in the transfer of copper between the metallochaperone and ATPase, could be stabilized by interactions with other MBDs, including a domain located in the loop between Mnk1 and Mnk2. An important result of this work is the apparent direct correlation between the difference in the fluctuations of the metal binding site loop in its apo and holo forms and the measured affinity of the MBD for copper. This difference decreases from Mnk1 to Mnk6, Mnk4, and Mnk2 in this order. The study of the exposure to the solvent of the metal and the residues of the metal binding loop of the MBDs also shows different behavior for each MBD. In particular, copper in serine-rich domain Mnk3 and largely fluctuating domain Mnk5 appears to be more solvent-exposed than in the other MBDs. In the second part of this work, we investigated the importance of electrostatics in the MBD-chaperone interactions using different docking programs. Mnk1 and Mnk4 present a large electrostatic dipole moment and large stabilizing interaction energies with HAH1. Finally, we propose a model structure of ATP7A from Mnk6 (E561) to P1413 based on the crystal structure of LpCopA and docking simulations.

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“…Force field parameters can be generated using different methods. Bond, angle, or dihedral values are varied while we determine the energetics. − The Hessian matrix using internal coordinates from frequency calculations can be utilized to compute the force constant values. − Nonetheless, these two methods yield force field parameters depending on the choice of internal coordinates. Thus, different simulation results can be obtained using different choices in internal coordinates.…”

Section: Computational Chemistry Studies Of Transition Metal–aβ Compl...mentioning

confidence: 99%

Transition Metal Ion Interactions with Disordered Amyloid-β Peptides in the Pathogenesis of Alzheimer’s Disease: Insights from Computational Chemistry Studies

Strodel

Coskuner‐Weber

2019

J. Chem. Inf. Model.

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Monomers and oligomers of the amyloid-β peptide aggregate to form the fibrils found in the brains of Alzheimer’s disease patients. These monomers and oligomers are largely disordered and can interact with transition metal ions, affecting the mechanism and kinetics of amyloid-β aggregation. Due to the disordered nature of amyloid-β, its rapid aggregation, as well as solvent and paramagnetic effects, experimental studies face challenges in the characterization of transition metal ions bound to amyloid-β monomers and oligomers. The details of the coordination chemistry between transition metals and amyloid-β obtained from experiments remain debated. Furthermore, the impact of transition metal ion binding on the monomeric or oligomeric amyloid-β structures and dynamics are still poorly understood. Computational chemistry studies can serve as an important complement to experimental studies and can provide additional knowledge on the binding between amyloid-β and transition metal ions. Many research groups conducted first-principles calculations, ab initio molecular dynamics simulations, quantum mechanics/classical mechanics simulations, and classical molecular dynamics simulations for studying the interplay between transition metal ions and amyloid-β monomers and oligomers. This review summarizes the current understanding of transition metal interactions with amyloid-β obtained from computational chemistry studies. We also emphasize the current view of the coordination chemistry between transition metal ions and amyloid-β. This information represents an important foundation for future metal ion chelator and drug design studies aiming to combat Alzheimer’s disease.

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In silico modeling of the Menkes copper-translocating P-type ATPase 3rd metal binding domain predicts that phosphorylation regulates copper-binding

Cited by 6 publications

References 44 publications

The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders

The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders

Dynamics and Stability of the Metal Binding Domains of the Menkes ATPase and Their Interaction with Metallochaperone HAH1

Transition Metal Ion Interactions with Disordered Amyloid-β Peptides in the Pathogenesis of Alzheimer’s Disease: Insights from Computational Chemistry Studies

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