Copper transporter 2 regulates intracellular copper and sensitivity to cisplatin

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Copper is a trace metal with a ready capacity to gain or donate electrons. This property is harnessed by numerous enzymes to perform vital functions in the body. In humans, copper is required for various biochemical processes, including cellular respiration, connective tissue development, iron transport and pigmentation. The same redox property that makes copper useful can also have deleterious effects if the proper balance is not maintained. Cellular copper homeostasis is maintained by several different proteins, including CTR1 (copper transporter 1), a high affinity copper importer, as well as ATP7A and ATP7B copper exporting ATPases. ATP7A controls the cellular export of copper and this function of ATP7A is largely regulated by its subcellular localization. Under low intracellular copper concentrations, ATP7A protein is localized to the TGN (trans-Golgi network), where it transports copper to newly synthesized cuproenzymes. Under elevated intracellular copper concentrations, ATP7A traffics to the plasma membrane, subsequently releasing its copper load by fusion with the plasma membrane. To maintain copper homeostasis, ATP7A undergoes constitutive trafficking between the TGN and the plasma membrane. Several key regions in the protein are required for its internalization and successful retrieval from the plasma membrane. Previous studies had shown that a single di-leucine motif in the cytoplasmic tail of ATP7A was required for its internalization. It is hypothesized that multiple di-leucines in the carboxy-terminus of ATP7A are involved in the internalization of the protein. The study presented in this thesis, identified a second di-leucine motif in ATP7A that is a bonafide sorting signal sequence required for internalization and maintaining the steady state localization of the protein. ... Taken together, these findings identify roles for the ATP7A copper transporter at the nexus of platinum-drug resistance, tumorigenesis and metastatic pathways, underscoring its potential as a therapeutic drug target at multiple stages of carcinogenesis.

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The copper transporter 1 (CTR1) is required to maintain the stability of copper transporter 2 (CTR2)

Metallomics ◽

10.1039/c5mt00131e ◽

2015 ◽

Vol 7 (11) ◽

pp. 1477-1487 ◽

Cited By ~ 10

Author(s):

Cheng-Yu Tsai ◽

Janika K. Liebig ◽

Igor F. Tsigelny ◽

Stephen B. Howell

Keyword(s):

Copper Transporter ◽

The Stability ◽

First Time ◽

Copper Transporter 2 ◽

Copper Transporter 1

We describe for the first time that the copper transporter 1 (CTR1) is important to maintain the stability of copper transporter 2 (CTR2).

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Mobilization of Intracellular Copper Stores by the Ctr2 Vacuolar Copper Transporter

Journal of Biological Chemistry ◽

10.1074/jbc.m411669200 ◽

2004 ◽

Vol 279 (52) ◽

pp. 54221-54229 ◽

Cited By ~ 140

Author(s):

Erin M. Rees ◽

Jaekwon Lee ◽

Dennis J. Thiele

Keyword(s):

Copper Transporter ◽

Intracellular Copper

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Copper Transporter 2 Regulates Endocytosis and Controls Tumor Growth and Sensitivity to Cisplatin In Vivo

Molecular Pharmacology ◽

10.1124/mol.110.068411 ◽

2010 ◽

Vol 79 (1) ◽

pp. 157-166 ◽

Cited By ~ 42

Author(s):

Brian G. Blair ◽

Christopher A. Larson ◽

Preston L. Adams ◽

Paolo B. Abada ◽

Catherine E. Pesce ◽

...

Keyword(s):

Tumor Growth ◽

Copper Transporter ◽

Copper Transporter 2

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Copper Transporter 2 Content Is Lower in Liver and Heart of Copper-Deficient Rats

International Journal of Molecular Sciences ◽

10.3390/ijms11114741 ◽

2010 ◽

Vol 11 (11) ◽

pp. 4741-4749 ◽

Cited By ~ 3

Author(s):

Jesse Bertinato ◽

Sébastien Duval ◽

Mary R. L’Abbé

Keyword(s):

Copper Transporter ◽

Copper Transporter 2

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

Molecular Biology of the Cell ◽

10.1091/mbc.e14-06-1073 ◽

2015 ◽

Vol 26 (1) ◽

pp. 91-103 ◽

Cited By ~ 102

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.

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

Open Biology ◽

10.1098/rsob.210128 ◽

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.

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Reconstruction of a helical trimer by the second transmembrane domain of human copper transporter 2 in micelles and the binding of the trimer to silver

RSC Advances ◽

10.1039/c5ra24889b ◽

2016 ◽

Vol 6 (6) ◽

pp. 4335-4342 ◽

Cited By ~ 1

Author(s):

Zhe Dong ◽

Liping Guan ◽

Chunyu Wang ◽

Haoran Xu ◽

Zhengqiang Li ◽

...

Keyword(s):

Intermolecular Interaction ◽

Transmembrane Domain ◽

Copper Transporter ◽

Lower Affinity ◽

Copper Transporter 2

The second transmembrane domain of human copper transporter 2 (hCtr2-TMD2) forms a trimer with a weaker intermolecular interaction and a lower affinity for Ag(I) than hCtr1-TMD2 trimer.

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