[Frontiers in Bioscience 14, 4878-4903, June 1, 2009]

Molecular mechanisms of copper homeostasis

Vasiliki Lalioti, Gemma Muruais, Yo Tsuchiya, Diego Pulido, Ignacio V. Sandoval

Centro de Biologia Molecular Severo Ochoa and Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Consejo Superior de Investigaciones Cientificas, Universidad Autonoma de Madrid, Cantoblanco 28049, Madrid, Spain

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Ctr1 and Cu uptake
4. GSH and metallothioneins, Cu sequestration and storage
5. Chaperone-based Cu homeostasis and distribution
5.1. Via to the Cu/Zn superoxidase dismutase Sod1
5.2. Via to mitochondrial cytochrome c oxidase (Cox)
5.2.1. Cox17
5.2.2. Sco1, Sco2 and CuA
5.2.3. Cox11and CuB.
5.3. Via to Cu-transporting ATPases
5.3.1. Atx1, Atox1
6. Cu-transporting ATPases
7. Dietary Cu uptake, store, distribution and export in the intestine
8. Cu circulation in the blood
9. Cu capture, storage and distribution in the liver, excretion through the bile
10. ATP7B dysfunction and Cu toxicosis
11. ATP7A dysfunction and Cu defficiency
12. Perspectives
13. Acknowledgments
14. References

1. ABSTRACT

The transition metal copper (Cu) is an essential trace element for all biota. Its redox properties bestow Cu with capabilities that are simultaneously essential and potentially damaging to the cell. Free Cu is virtually absent in the cell. The descriptions of the structural and functional organization of the metallothioneins, Cu-chaperones and P-type ATPases as well as of the mechanisms that regulate their distribution and functioning in the cell have enormously advanced our understanding of the Cu homeostasis and metabolism in the last decade. Cu is stored by metallothioneins and distributed by specialized chaperones to specific cell targets that make use of its redox properties. Transfer of Cu to newly synthesized cuproenzymes and Cu disposal is performed by the individual or concerted actions of the P-type ATPases ATP7A and ATP7B expressed in tissues. In mammalians liver is the major captor, distributor and excreter of Cu. Mutations in the P-type ATPases that interfere with their functioning and traffic are cause of the life-threatening Wilson (ATP7B) and Menkes (ATP7A) diseases.