Function and Regulation of Human Copper-Transporting ATPases

Abstract

Copper-transporting ATPases (Cu-ATPases) ATP7A and ATP7B are evolutionarily conserved polytopic membrane proteins with essential roles in human physiology. The Cu-ATPases are expressed in most tissues, and their transport activity is crucial for central nervous system development, liver function, connective tissue formation, and many other physiological processes. The loss of ATP7A or ATP7B function is associated with severe metabolic disorders, Menkes disease, and Wilson disease. In cells, the Cu-ATPases maintain intracellular copper concentration by transporting copper from the cytosol across cellular membranes. They also contribute to protein biosynthesis by delivering copper into the lumen of the secretory pathway where metal ion is incorporated into copper-dependent enzymes. The biosynthetic and homeostatic functions of Cu-ATPases are performed in different cell compartments; targeting to these compartments and the functional activity of Cu-ATPase are both regulated by copper. In recent years, significant progress has been made in understanding the structure, function, and regulation of these essential transporters. These studies raised many new questions related to specific physiological roles of Cu-ATPases in various tissues and complex mechanisms that control the Cu-ATPase function. This review summarizes current data on the structural organization and functional properties of ATP7A and ATP7B as well as their localization and functions in various tissues, and discusses the current models of regulated trafficking of human Cu-ATPases.

Mechanism of Cu+-transporting ATPases: Soluble Cu+chaperones directly transfer Cu+to transmembrane transport sites

“…Cu ϩ -ATPases are essential to maintain Cu ϩ homeostasis. For instance, mutations in the two Cu ϩ -ATPase genes present in humans, ATP7A and ATP7B, lead to Menkes syndrome and Wilson's disease, respectively (8,9). The Cu ϩ -ATPases transport cycle follows the classical E1/E2 Albers-Post model (10)(11)(12).…”

“…In bacterial Cu ϩ -ATPases, deletion of these domains or mutation of Cu ϩ -binding Cys residues does not prevent metal activation of the ATPase, although they affect enzyme turnover rate (15,16,19). Significantly, N-MBDs appear necessary for ATPase metal-dependent targeting and localization in eukaryote systems (9). Invariant amino acids present in transmembrane helices H6 (two Cys), H7 (Asn, Tyr), and H8 (Met, Ser) constitute the TM-MBS (Fig.…”

Unresolved questions in human copper pump mechanisms

“…During the catalytic cycle, that requires ATP hydrolysis and ultimately results in Cu transfer to the lumen side of the membrane, ATP7A/B are likely to undergo significant conformational changes driven by domain-domain interactions (Lutsenko et al 2007). Available predictions for how ATP7A/B works catalytically come from analogy with the calcium pump SERCA, for which structures of different enzymatic stages have been resolved (Bublitz et al 2013).…”

“…1). In addition, ATP7A and ATP7B both have six cytoplasmic metal-binding domains in the N-terminus connected by peptide linkers of various lengths (Lutsenko et al 2007). Notably, much of our current knowledge of ATP7A/B comes from studies of individual domains (as it is difficult to prepare the full length proteins) and from work on yeast and bacterial homologs (Culotta et al 2005;Gourdon et al 2011).…”

Copper-trafficking efficacy of copper-pyruvaldehyde bis(N4-methylthiosemicarbazone) on the macular mouse, an animal model of Menkes disease

“…ATP7A is expressed in most cell types, although not in hepatocytes (1), and is located primarily in the trans-Golgi network, where it transports copper in from the cytosol (2). Under conditions in which copper levels are elevated, ATP7A relocalizes to the plasma membrane to expel copper from the cell.…”