Mammalian copper-transporting P-type ATPases, ATP7A and ATP7B: emerging roles

Abstract

Copper (Cu) has a role in a diverse and increasing number of pathways, physiological and disease processes. These roles are testament to the fundamental importance of Cu in biology and the need to understand the mechanisms that regulate Cu homeostasis. The mammalian Cu-transporting P-type ATPases ATP7A and ATP7B are two key proteins that regulate the Cu status of the body. They transport Cu across cellular membranes for biosynthetic and protective functions, enabling Cu to fulfill its role as a catalytic and structural cofactor for many essential enzymes, and to prevent a toxic build-up of Cu inside cells. A variety of regulatory mechanisms operate at transcriptional and post-translational levels to ensure adequate Cu supplies for both physiological and pathophysiological processes. This review summarizes the recent literature that is revealing the emerging roles of the Cu-ATPases in health and disease.

Figure 1

Schematic diagram of the structure of the Cu-ATPases, ATP7A and ATP7B. The eight transmembrane domains that form the channel for Cu translocation are shown in blue. The N and C termini on the cytoplasmic side of the membrane are indicated, as are the conserved Cu-binding motifs (CxxC) of the six metal binding domains (MBD) within the N terminus. The intramembrane Cys-Pro-Cys motif that is required for Cu translocation through the membrane is also shown. The key conserved sequences of the N-domain (containing the ATP binding site), the P-domain (containing the conserved aspartic acid residue) and the A-domain (comprising the phosphatase domain) (Lutsenko et al., 2007) are shown.

Figure 2

Emerging roles of the mammalian Cu-ATPases. Schematic representation of the physiological and pathophysiological processes, so far known to depend upon the activities of ATP7A and ATP7B. Ovals without shading represent pathophysiological processes in which the activity of the Cu-ATPases may be beneficial or protective, whereas the dark grey shaded ovals represent disease processes that are exacerbated by Cu-ATPase activity.