Copper binding leads to increased dynamics in the regulatory N-terminal domain of full-length human copper transporter ATP7B

Orädd, Fredrik; Steffen, Jonas Hyld; Gourdon, Pontus; Andersson, Magnus

doi:10.1371/journal.pcbi.1010074

Cited by 5 publications

(7 citation statements)

References 82 publications

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“…The change to a G at this position segregated with the coat color phenotype; sequences from an affected male and a second affected female are shown (Figure 2E, F). Amino acid 610 lies between the 6 th of six metal binding domains in Atp7a and the first transmembrane domain, a position of functional importance based on previous studies 42,43 .…”

Section: Resultsmentioning

confidence: 94%

Alpha-synuclein null mutation exacerbates the phenotype of a model of Menkes disease in female mice

Casey,

Zou,

Pera

et al. 2023

Preprint

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Genetic modifier screens provide a useful tool, in diverse organisms fromDrosophilatoC. elegansand mice, for recovering new genes of interest that may reduce or enhance a phenotype of interest. This study reports a modifier screen, based on N-ethyl-N-nitrosourea (ENU) mutagenesis and outcrossing, designed to increase understanding of the normal function of murine α-synuclein (Snca). HumanSNCAwas the first gene linked to familial Parkinson’s disease. Since the discovery of the genetic link ofSNCAto Parkinson’s nearly three decades ago, numerous studies have investigated the normal function of SNCA protein with divergent roles associated with different cellular compartments. Understanding of the normal function of murine Snca is complicated by the fact that mice with homozygous null mutations live a normal lifespan and have only subtle synaptic deficits. Here, we report that the first genetic modifier (a sensitized mutation) that was identified in our screen was the X-linked gene,ATPase copper transporting alpha (Atp7a).In humans, mutations inAtp7aare linked to to Menkes disease, a disease with pleiotropic phenotypes that include a severe neurological component.Atp7aencodes a trans-Golgi copper transporter that supplies the copper co-factor to enzymes that pass through the ER-Golgi network. Male mice that carry a mutation inAtp7adie within 3 weeks of age regardless ofSncagenotype. In contrast, here we show thatSncadisruption modifies the phenotype ofAtp7ain female mice. Female mice that carry theAtp7amutation, on anSncanull background, die earlier (prior to 35 days) at a significantly higher rate than those that carry theAtp7amutation on a wildtypeSncabackground ATPase copper transporting alpha. Thus,Sncanull mutations sensitize female mice to mutations inAtp7a,suggesting that Snca protein may have a protective effect in females, perhaps in neurons, given the co-expression patterns. Although data has suggested diverse functions for human and mouse α-synuclein proteins in multiple cell compartments, this is the first demonstration via use of genetic screening to demonstrate that Snca protein may function in the ER-Golgi system in the mammalian brain in a sex-dependent manner.Author summaryThis study sought to probe the normal function(s) of a protein associated with Parkinson’s disease, the second most common neurodegenerative disease in humans. We used a genetic modifier approach to uncover aspects of normal protein function, via mutagenesis of mice and screening for neurological problems that are decreased or enhanced in mice that are null for α-synuclein (Snca). Through these studies, we identified the X-linked gene that is mutated in Menkes disease in humans as a modifier of the nullSncaphenotype, specifically in female mice. The gene mutated in Menkes disease,ATP7a, encodes a copper transporter that is known to act in the trans-Golgi sub-cellular compartment. Genetic modifier effects suggest that Snca may also play a role in that compartment, potentially in the mammalian brain.

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Section: Resultsmentioning

confidence: 94%

Alpha-synuclein null mutation exacerbates the phenotype of a model of Menkes disease in female mice

Casey,

Zou,

Pera

et al. 2023

Preprint

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“…The wealth of states seen in Figure 3 suggests that Atox1 can adopt multiple states in its low coordination states to interact with other Cu‐binding proteins to facilitate metal ion transport. Recent work has shown a connection between Cu(I) binding and flexibility of the human copper‐transporting protein ATP7B which interacts with Atox1 39 …”

Section: Resultsmentioning

confidence: 99%

“…Recent work has shown a connection between Cu(I) binding and flexibility of the human copper-transporting protein ATP7B which interacts with Atox1. 39…”

Section: Mutual Rmsd-based Clusteringmentioning

confidence: 99%

Copper coordination states affect the flexibility of copper Metallochaperone Atox1: Insights from molecular dynamics simulations

2022

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Copper is an essential element in nature but in excess, it is toxic to the living cell. The human metallochaperone Atox1 participates in copper homeostasis and is responsible for copper transmission. In a previous multiscale simulation study, we noticed a change in the coordination state of the Cu(I) ion, from 4 bound cysteine residues to 3, in agreement with earlier studies. Here, we perform and analyze classical molecular dynamic simulations of various coordination states: 2, 3, and 4. The main observation is an increase in protein flexibility as a result of a decrease in the coordination state. In addition, we identified several populated conformations that correlate well with double electron-electron resonance distance distributions or an X-ray structure of Cu(I)-bound Atox1.We suggest that the increased flexibility might benefit the process of ion transmission between interacting proteins. Further experiments can scrutinize this hypothesis and shed additional light on the mechanism of action of Atox1.

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“…53 Copper binding results in elevated dynamics in the regulatory N-terminal domains of ATP7B. 54 The sites are essential for the activity and copper-modulated intracellular redistribution of ATP7B. 55 Several proteins are capable of interaction with the ATP7B N terminus.…”

Section: Copper Exportmentioning

confidence: 99%

“…The N‐terminal position of ATP7B comprises six metal‐binding domains, each with a copper‐binding motif, MXCXXC 53 . Copper binding results in elevated dynamics in the regulatory N‐terminal domains of ATP7B 54 . The sites are essential for the activity and copper‐modulated intracellular redistribution of ATP7B 55 .…”

Section: Copper Metabolismmentioning

confidence: 99%

Copper homeostasis and cuproptosis in cancer immunity and therapy

Liu,

Lin,

Yan

et al. 2023

Immunological Reviews

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SummaryCopper is an essential nutrient for maintaining enzyme activity and transcription factor function. Excess copper results in the aggregation of lipoylated dihydrolipoamide S‐acetyltransferase (DLAT), which correlates to the mitochondrial tricarboxylic acid (TCA) cycle, resulting in proteotoxic stress and eliciting a novel cell death modality: cuproptosis. Cuproptosis exerts an indispensable role in cancer progression, which is considered a promising strategy for cancer therapy. Cancer immunotherapy has gained extensive attention owing to breakthroughs in immune checkpoint blockade; furthermore, cuproptosis is strongly connected to the modulation of antitumor immunity. Thus, a thorough recognition concerning the mechanisms involved in the modulation of copper metabolism and cuproptosis may facilitate improvement in cancer management. This review outlines the cellular and molecular mechanisms and characteristics of cuproptosis and the links of the novel regulated cell death modality with human cancers. We also review the current knowledge on the complex effects of cuproptosis on antitumor immunity and immune response. Furthermore, potential agents that elicit cuproptosis pathways are summarized. Lastly, we discuss the influence of cuproptosis induction on the tumor microenvironment as well as the challenges of adding cuproptosis regulators to therapeutic strategies beyond traditional therapy.

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Copper binding leads to increased dynamics in the regulatory N-terminal domain of full-length human copper transporter ATP7B

Cited by 5 publications

References 82 publications

Alpha-synuclein null mutation exacerbates the phenotype of a model of Menkes disease in female mice

Alpha-synuclein null mutation exacerbates the phenotype of a model of Menkes disease in female mice

Copper coordination states affect the flexibility of copper Metallochaperone Atox1: Insights from molecular dynamics simulations

Copper homeostasis and cuproptosis in cancer immunity and therapy

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