Copper(II) import and reduction are dependent on His-Met clusters in the extracellular amino terminus of human copper transporter-1

Abstract

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Cuproptosis: mechanisms and links with cancers

“…CTR1 mainly transports monovalent copper ions. After being transported to the cell surface in the blood, divalent copper ions are reduced to monovalent copper ions catalyzed by steap proteins [ 32 ], which are bound and maintained in the reduced state by two His-Met-Asp clusters at the nitrogen terminus of CTR [ 33 ], and thus transported into the cell. Cu was transported from the intermembrane space of mitochondria across the inner membrane into the mitochondrial matrix by the transmembrane transport protein solute carrier family 25 member 3 (SLC25A3) [ 34 ].…”

The Molecular Mechanisms of Defective Copper Metabolism in Diabetic Cardiomyopathy

“…Ablation of CTR2 reduces the generation of truncated CTR1 lacking a copper-binding echo domain and, thus, increases tissue copper contents [ 88 ]. Its abundance and location determine the rate of copper import [ 89 ] and regulate the redox state of Cu + [ 90 ], playing an important role in regulating intracellular copper homeostasis and copper bioavailability. In the presence of excess copper, CTR1 can be internalized from the plasma membrane into the endocytic body [ 90 ] to protect cells from copper poisoning.…”

“…Its abundance and location determine the rate of copper import [ 89 ] and regulate the redox state of Cu + [ 90 ], playing an important role in regulating intracellular copper homeostasis and copper bioavailability. In the presence of excess copper, CTR1 can be internalized from the plasma membrane into the endocytic body [ 90 ] to protect cells from copper poisoning. Endosomal CTR1 can then be degraded by the proteasome or recycled back to the plasma membrane [ 91 ].…”

Properties of recombinant extracellular N-terminal domain of human high-affinity copper transporter 1 (hNdCTR1) and its interactions with Cu(ii) and Ag(i) ions

“…51,52 The key Met residues are also required for copper-stimulated endocytosis and degradation of the CTR1 protein. 53 The extremely short extracellular loop between helices 2 and 3 brings them together and facilitates the formation of the pore and extracellular Met/His clusters, which are critical for copper import. Long cytosolic loop facilitates Cu(I) transfer to intracellular copper chaperones.…”