Copper TransportingATPases in Mammalian Cells

Abstract

Copper‐transporting ATP ases ( Cu‐ATPases ) are essential for growth and development of mammalian organisms. These ubiquitous and evolutionarily conserved transporters participate in the biosynthesis of copper‐dependent enzymes and maintain copper levels within the range necessary to meet metabolic demands and avoid toxicity. Cu‐ATPases are the key components of sophisticated cellular machinery that evolved to provide precise inter‐ and intracellular distribution of metals, and the function of these transporters is tightly regulated. Copper along with a growing number of cytosolic proteins controls the activity, stability, and localization of Cu‐ATPases ; this regulation ensures balance between the delivery of copper to metalloenzymes in various cell compartments and copper export. Inactivating mutations in human Cu‐ ATPases ATP7A and ATP7B are associated with debilitating and often lethal disorders (Menkes disease and Wilson's disease, respectively). Biochemical and biophysical studies of ATP7A and ATP7B revealed multiple metal‐binding sites, complex multi‐domain architecture, and a significant role of interdomain interactions in the function and regulation of these transporters. This article summarizes the current data on the structure and mechanism of human Cu‐ ATPases ATP7A and ATP7B , as well as the biochemical basis of their regulation.