Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway

Hatori, Yoshinori; Yan, Ye; Schmidt, Katharina; Furukawa, Eri; Hasan, Nesrin M.; Yang, Nan; Liu, Chin Nung; Sockanathan, Shanthini; Lutsenko, Svetlana

doi:10.1038/ncomms10640

Cited by 90 publications

(104 citation statements)

References 51 publications

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“…If there are no copper chaperones in the lumen of the secretory pathway, copper delivery may be the key step. Using a neuroblastoma cell line, data supporting the hypothesis that cytosolic copper binding proteins serve as a reservoir of copper that can be delivered by Atp7a when needed were recently reported 21 .…”

Section: Discussionmentioning

confidence: 73%

“…Similarly, a study of SH-SY5Y neuroblastoma cells reported very similar copper levels in whole cell lysates and in fractions enriched in microsomes 21 . One of the only earlier studies analyzing purified secretory granules reported levels of copper in adrenal chromaffin granules (0.6 nmol Cu/mg chromaffin granule protein) 38 that are very similar to the levels found here for pituitary granules.…”

Section: Discussionmentioning

confidence: 76%

“…Copper targeted to the secretory pathway binds to Atox1, which transfers the metal to Atp7a, the P-type ATPase that delivers it into the lumen of the secretory pathway 34 . Recent studies indicate that this transport process is facilitated with more reducing cytosolic conditions 21 . Most of the copper measurements available in the literature report total copper levels.…”

Section: Discussionmentioning

confidence: 99%

“…Quantitative Western blot analysis was used to compare levels of PAM in secretory granules to levels of the three metals it requires. Recent studies suggesting signaling roles for labile cytosolic copper pools 19, 20 , redox-regulated flux of copper into the secretory pathway 21 and the direct transfer of copper from Atp7a to its target luminal cuproenzymes 22 require better knowledge of copper levels in specific subcellular organelles.…”

Section: Introductionmentioning

confidence: 99%

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Copper, zinc and calcium: imaging and quantification in anterior pituitary secretory granules

et al. 2016

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The anterior pituitary is specialized for the synthesis, storage and release of peptide hormones. The activation of inactive peptide hormone precursors requires a specific set of proteases and other post-translational processing enzymes. High levels of peptidylglycine α-amidating monooxygenase (PAM), an essential peptide processing enzyme, occur in the anterior pituitary. PAM, which converts glycine-extended peptides into amidated products, requires copper and zinc to support its two catalytic activities and calcium for structure. We used X-ray fluorescence microscopy on rat pituitary sections and inductively coupled plasma mass spectrometry on subcellular fractions prepared from rat anterior pituitary to localize and quantify copper, zinc and calcium. X-ray fluorescence microscopy indicated that the calcium concentration in pituitary tissue was about 2.5 mM, 10-times more than zinc and 50-times more than copper. Although no higher than cytosolic levels, secretory granule levels of copper exceeded PAM levels by a factor of 10. Atp7a, which transports copper into the lumen of the secretory pathway, was enriched in endosomes and Golgi, not in secretory granules. If Atp7a transfers copper directly to PAM, this pH-dependent process is likely to occur in endosomes.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Copper, zinc and calcium: imaging and quantification in anterior pituitary secretory granules

et al. 2016

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“…GSH can also modulate copper delivery and flux through individual trafficking pathways via PTM of protein function. Thus far, the secretory pathway has received the most attention in this regard with glutathionylation impairing the activity of the soluble chaperone ATOX1 and the TGN ATPases ATP7A and ATP7B, 103–105 and deglutathionylation of these proteins rendering their cysteines accessible to copper and stimulating copper delivery to the secretory pathway.…”

Section: Mitochondria Redox Regulation and Control Of Copper Homeostmentioning

confidence: 99%

The mitochondrion: a central architect of copper homeostasis

2017

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All known eukaryotes require copper for their development and survival. The essentiality of copper reflects its widespread use as a co-factor in conserved enzymes that catalyze biochemical reactions critical to energy production, free radical detoxification, collagen deposition, neurotransmitter biosynthesis and iron homeostasis. However, the prioritized use of copper poses an organism with a considerable challenge because, in its unbound form, copper can potentiate free radical production and displace iron-sulphur clusters to disrupt protein function. Protective mechanisms therefore evolved to mitigate this challenge and tightly regulate the acquisition, trafficking and storage of copper such that the metal ion is rarely found in its free form in the cell. Findings by a number of groups over the last ten years emphasize that this regulatory framework forms the foundation of a system that is capable of monitoring copper status and reprioritizing copper usage at both the cellular and systemic levels of organization. While the identification of relevant molecular mechanisms and signaling pathways has proven to be difficult and remains a barrier to our full understanding of the regulation of copper homeostasis, mounting evidence points to the mitochondrion as a pivotal hub in this regard in both healthy and diseased states. Here, we review our current understanding of copper handling pathways contained within the organelle and consider plausible mechanisms that may serve to functionally couple their activity to that of other cellular copper handling machinery to maintain copper homeostasis.

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Dynamics of the metal binding domains and regulation of the human copper transporters ATP7B and ATP7A

Dolgova

Dmitriev

2017

IUBMB Life

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Copper transporters ATP7A and ATP7B regulate copper levels in the human cells and deliver copper to the biosynthetic pathways. ATP7A and ATP7B belong to the P-type ATPases and share much of the domain architecture and the mechanism of ATP hydrolysis with the other, well-studied, enzymes of this type. A unique structural feature of the copper ATPases is the chain of six cytosolic metal-binding domains (MBDs), which are believed to be involved in copper-dependent regulation of the activity and intracellular localization of these enzymes. Although the structures of all the MBDs have been solved, the mechanism of copper-dependent regulation of ATP7B and ATP7A, the roles of individual MBDs, and the relationship between the regulatory and catalytic copper binding are still unknown. We describe the structure and dynamics of the MBDs, review the current knowledge about their functional roles and propose a mechanism of regulation of ATP7B by copper-dependent changes in the dynamics and conformation of the MBD chain. Transient interactions between the MBDs, rather than transitions between distinct static conformations are likely to form the structural basis of regulation of the ATPdependent copper transporters in human cells. V C 2017 IUBMB Life, 69(4): [226][227][228][229][230][231][232][233][234][235] 2017

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Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway

Cited by 90 publications

References 51 publications

Copper, zinc and calcium: imaging and quantification in anterior pituitary secretory granules

Copper, zinc and calcium: imaging and quantification in anterior pituitary secretory granules

The mitochondrion: a central architect of copper homeostasis

Dynamics of the metal binding domains and regulation of the human copper transporters ATP7B and ATP7A

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