Copper‐transporting ATPases: The evolutionarily conserved machineries for balancing copper in living systems

Abstract

Copper ATPases (Cu-ATPases) are ubiquitous transmembrane proteins using energy from ATP to transport copper across different biological membranes of prokaryotic and eukaryotic cells. As they belong to the P-ATPase family, Cu-ATPases contain a characteristic catalytic domain with an evolutionarily conserved aspartate residue phosphorylated by ATP to form a phosphoenzyme intermediate, as well as transmembrane helices containing a cation-binding cysteine-proline-cysteine/histidine/serine (CPx) motif for catalytic activation and cation translocation. In addition, most Cu-ATPases possess the N-terminal Cu-binding CxxC motif required for regulation of enzyme activity. In cells, the Cu-ATPases receive copper from soluble chaperones and maintain intracellular copper homeostasis by efflux of copper from the cell or transport of the metal into the intracellular compartments. In addition, copper pumps play an essential role in cuproprotein biosynthesis by the uptake of copper into the cell or delivery of the metal into the chloroplasts and thylakoid lumen or into the lumen of the secretory pathway, where the metal ion is incorporated into copper-dependent enzymes. In the recent years, significant progress has been made toward understanding the function and regulation of Cu-transporting ATPases in archaea, bacteria, yeast, humans, and plants, providing new insights into the specific physiological roles of these essential proteins in various organisms and revealing some conservative regulatory mechanisms of Cu-ATPase activity. In this review, the structural, biochemical, and functional properties of Cu-ATPases from phylogenetically different organisms are summarized and discussed, with particular attention given to the recent insights into the molecular biology of copper pumps in plants. V C 2015 IUBMB Life, 67(10):737-745, 2015

Copper Resistance in Aspergillus nidulans Relies on the PI-Type ATPase CrpA, Regulated by the Transcription Factor AceA

“…As shown in Figure 1A, bioinformatic analyses predicted in CrpA the presence of the distinctive domains described for well-studied copper-transporting ATPases of yeast, human, bacteria and archaea (Solioz and Odermatt, 1995; Mandal et al, 2002; Barry et al, 2010; Rosenzweig and Argüello, 2012; Migocka, 2015; Smith et al, 2016; Figure 1A); 8 transmembrane domains (TM), a conserved CPC copper translocation motif placed in the 6th TM segment and cysteine rich metal binding motifs (MBD) in the cytoplasmic N-terminal. 5 N-MBD are predicted as tandem repeats, 2 CxxC motifs located closer to the amino terminus followed by 3 GMxCxxC classical heavy metal associated domains (HMA).…”

Programmed Ribosomal Frameshifting Generates a Copper Transporter and a Copper Chaperone from the Same Gene

“…Disruption of copper homeostasis has been linked to human maladies e.g., Menkes, Wilson, and Parkinson diseases as well as cystic fibrosis (Bull et al, 1993; Percival et al, 1999; Torsdottir et al, 1999; Vulpe et al, 1993). Sophisticated systems have evolved to maintain copper homeostasis in bacterial and eukaryotic cells (Fan and Rosen, 2002; Outten and O'Halloran, 2001), in which the central role belongs to copper-translocating ATPases responsible for export of excess copper ions from the cell (Fan and Rosen, 2002; Migocka, 2015). …”

Copper in the suprachiasmatic circadian clock: A possible link between multiple circadian oscillators

“…Changes in cellular redox state in turn can influence membrane excitability, such as through modulating K + currents. Cu has been shown to interact with extracellular and intracellular signal transduction mechanisms, including modulating NMDA, MAPK, and TrkB signaling, a variety of ion channels, and extracellular matrix/proteases (e.g., collagen lyase, PAI‐1), all of which again can alter membrane excitability (Bucci et al., , ; D'Ambrosi & Rossi, ; Fujie et al., ; Migocka, ; Scheiber et al., ; Urso & Maffia, ; Zlatic et al., ). Our data are consistent with this, showing Cu/Cu depletion‐induced effects involving NMDA, MAPK, TrkB, and NO.…”

“…Thus, there are several mechanisms for buffering, storing, and removing intracellular Cu. In mammals, two P‐type ATPases, ATP7A and ATP7B, have a prominent role in intracellular Cu homeostasis and transport (Lutsenko, ; Migocka, ; Yu et al., ). Mutations in ATP7A disrupt Cu absorption in the gut and intracellular delivery to Cu‐dependent enzymes, resulting in Menkes disease (Kaler, ; Lenartowicz et al., ; Zlatic et al., ).…”