Copper trafficking in eukaryotic systems: current knowledge from experimental and computational efforts

Magistrato, Alessandra; Pavlin, Matic; Qasem, Zena; Ruthstein, Sharon

doi:10.1016/j.sbi.2019.05.002

Cited by 38 publications

(38 citation statements)

References 58 publications

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“…Consistent with these findings, K60 is well known as a critical residue for the interaction and stability of the complex [54], as well as for the transport mechanism of Cu(I) from Atox1 to MBD4. Moreover, we showed that the change in the protonation state of the metal-binding motif, known to affect transport [55], was most likely different in the presence of Cys-to-Ser mutations. This strikingly affected the structural, and possibly the functional, properties of the hosting proteins, which is consistent with the differences observed in CW-EPR spectra and the cross-linking experiments.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, both the experimental and the simulation data consistently showed that Cu(I) can still bind to proteins after the Cys-to-Ser mutations. In addition, molecular simulations revealed that along the metal transport route mediated by Atox1-ATP7B the serine residues will most likely remain protonated, or if deprotonated, they would most likely easily sequester a proton from K60, a critically important residue for adduct stability, as indicated by mutagenesis studies [55]. This would either hamper the metal’s release from Atox1 to the target MBD4 protein or affect the stability of the Atox1-ATP7B adduct.…”

Section: Discussionmentioning

confidence: 99%

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Unraveling the Impact of Cysteine-to-Serine Mutations on the Structural and Functional Properties of Cu(I)-Binding Proteins

Pavlin

Qasem

Sameach

et al. 2019

IJMS

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Appropriate maintenance of Cu(I) homeostasis is an essential requirement for proper cell function because its misregulation induces the onset of major human diseases and mortality. For this reason, several research efforts have been devoted to dissecting the inner working mechanism of Cu(I)-binding proteins and transporters. A commonly adopted strategy relies on mutations of cysteine residues, for which Cu(I) has an exquisite complementarity, to serines. Nevertheless, in spite of the similarity between these two amino acids, the structural and functional impact of serine mutations on Cu(I)-binding biomolecules remains unclear. Here, we applied various biochemical and biophysical methods, together with all-atom simulations, to investigate the effect of these mutations on the stability, structure, and aggregation propensity of Cu(I)-binding proteins, as well as their interaction with specific partner proteins. Among Cu(I)-binding biomolecules, we focused on the eukaryotic Atox1-ATP7B system, and the prokaryotic CueR metalloregulator. Our results reveal that proteins containing cysteine-to-serine mutations can still bind Cu(I) ions; however, this alters their stability and aggregation propensity. These results contribute to deciphering the critical biological principles underlying the regulatory mechanism of the in-cell Cu(I) concentration, and provide a basis for interpreting future studies that will take advantage of cysteine-to-serine mutations in Cu(I)-binding systems.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Unraveling the Impact of Cysteine-to-Serine Mutations on the Structural and Functional Properties of Cu(I)-Binding Proteins

Pavlin

Qasem

Sameach

et al. 2019

IJMS

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“…SLC31A1 is primarily expressed at the cell membrane and drives the uptake of copper from food in a potassium-dependent manner [478,480]. Copper homeostasis is critical for cells, as many enzymes are dependent on it for proper function [481].…”

Section: Slc30/slc39mentioning

confidence: 99%

A guide to plasma membrane solute carrier proteins

2020

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This review aims to serve as an introduction to the solute carrier proteins (SLC) superfamily of transporter proteins and their roles in human cells. The SLC superfamily currently includes 458 transport proteins in 65 families that carry a wide variety of substances across cellular membranes. While members of this superfamily are found throughout cellular organelles, this review focuses on transporters expressed at the plasma membrane. At the cell surface, SLC proteins may be viewed as gatekeepers of the cellular milieu, dynamically responding to different metabolic states. With altered metabolism being one of the hallmarks of cancer, we also briefly review the roles that surface SLC proteins play in the development and progression of cancer through their influence on regulating metabolism and environmental conditions.

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“…Recently, we conducted electron paramagnetic resonance (EPR) spectroscopy experiments in order to better understand the interaction between the Atox1 metallochaperone and MBD3-4 as a function of Cu(I) binding [23,25]. The power of EPR spectroscopy lies in its ability to target conformational changes in solution, without limiting the protein size or the system.…”

Section: Introductionmentioning

confidence: 99%

An EPR Study on the Interaction between the Cu(I) Metal Binding Domains of ATP7B and the Atox1 Metallochaperone

Zaccak

Qasem

Gevorkyan‐Airapetov

et al. 2020

IJMS

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Copper’s essentiality and toxicity mean it requires a sophisticated regulation system for its acquisition, cellular distribution and excretion, which until now has remained elusive. Herein, we applied continuous wave (CW) and pulsed electron paramagnetic resonance (EPR) spectroscopy in solution to resolve the copper trafficking mechanism in humans, by considering the route travelled by Cu(I) from the metallochaperone Atox1 to the metal binding domains of ATP7B. Our study revealed that Cu(I) is most likely mediated by the binding of the Atox1 monomer to metal binding domain 1 (MBD1) and MBD4 of ATP7B in the final part of its extraction pathway, while the other MBDs mediate this interaction and participate in copper transfer between the various MBDs to the ATP7B membrane domain. This research also proposes that MBD1-3 and MBD4-6 act as two independent units.

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Copper trafficking in eukaryotic systems: current knowledge from experimental and computational efforts

Abstract: Graphical abstract

Cited by 38 publications

References 58 publications

Unraveling the Impact of Cysteine-to-Serine Mutations on the Structural and Functional Properties of Cu(I)-Binding Proteins

Unraveling the Impact of Cysteine-to-Serine Mutations on the Structural and Functional Properties of Cu(I)-Binding Proteins

A guide to plasma membrane solute carrier proteins

An EPR Study on the Interaction between the Cu(I) Metal Binding Domains of ATP7B and the Atox1 Metallochaperone

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