Molecular mechanisms of copper homeostasis

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.

Bacterial Copper Resistance and Virulence

“…Failure in copper homeostasiscan lead to several human diseases such as Menkes syndrome, Wilson's disease, as well as Parkinson and Alzheimer's diseases [8][9][10]. The toxicity of Cu has been linked to different mechanisms.…”

Basolateral sorting and transcytosis define the Cu+-regulated translocation of ATP7B to the bile canaliculus

“…Thus, as the cell only needs Cu + in trace amounts, to counter the relative high levels of Cu + in food, animals have developed sophisticated mechanisms to chaperone, store and eliminate excess Cu + . In the liver, hepatocytes act as the major captor of the Cu + absorbed in the digestive tract, the main reservoir and distributor of Cu + to other tissues and organs, as well as the key mediator of Cu + elimination through excretion into bile (Harris, 2000;Lalioti et al, 2009). Because of these three functionalities, the liver plays an essential role in Cu + homeostasis in mammals, birds and reptiles.…”

Gene Expression Signatures Defining Fundamental Biological Processes in Pluripotent, Early, and Late Differentiated Embryonic Stem Cells

“…[71]). The copper-translocating ATP7A is involved in the Cu 2 + homeostasis and in the biosynthetic incorporation of Cu into copper-dependent enzymes that are essential for the secretory pathway, Cu detoxification via Cu efflux, and mutations in ATP7 are associated with Menkes disease [72,73].…”