Cellular copper distribution: a mechanistic systems biology approach

Abstract

Copper is an essential but potentially harmful trace element required in many enzymatic processes involving redox chemistry. Cellular copper homeostasis in mammals is predominantly maintained by regulating copper transport through the copper import CTR proteins and the copper exporters ATP7A and ATP7B. Once copper is imported into the cell, several pathways involving a number of copper proteins are responsible for trafficking it specifically where it is required for cellular life, thus avoiding the release of harmful free copper ions. In this study we review recent progress made in understanding the molecular mechanisms of copper transport in cells by analyzing structural features of copper proteins, their mode of interaction, and their thermodynamic and kinetic parameters, thus contributing to systems biology of copper within the cell.

The Mechanism of Cu+ Transport ATPases

“…As such, this has received significant attention (4,12,20,42). Biochemical studies have helped us to understand how the chaperone delivers Cu ϩ directly to both TM-MBSs present in Cu ϩ -ATPases (10,24).…”

“…Several lines of evidence further support the idea that electrostatics drive the CopZ⅐Cu ϩ /CopA interaction through the platform region. The involvement of complementary electrostatic surfaces has been shown for the interaction of Cu ϩ chaperones with target Cu,Zn-superoxide dismutases and, most importantly, the regulatory cytoplasmic MBDs in Cu ϩ -ATPases (20,42,43). For instance, the yeast Atx1 chaperone has several exposed electropositive residues (Lys-24, Lys-28, Lys-61, and Lys-62) adjacent to the MXCXXC Cu ϩ -binding site that may participate in the interaction with the yeast Ccc2 ATPase, because mutation of these residues inter- Negatively charged residues are indicated in red.…”

“…In the case of transition metals, water is unlikely a part of this process, considering the high Cu ϩ affinity of CopZ and the fact that Cu ϩ should remain protein-bound to prevent release into the media. Moreover, ligand exchange is the mechanism for Cu ϩ transfer among chaperone and MBDs (20,42,43). The LpCopA structure and our results suggest that Cu ϩ release from the chaperone requires the coordination of the metal by three invariant residues: Met, Glu, and Asp.…”

Effects of astaxanthin on oxidative stress induced by Cu2+ in prostate cells

“…Low intracellular Cu 2+ concentrations could influence the activities of these enzymes and the normal metabolisms of the cells. Interestingly, the redox properties of the metal also mediate its toxicity because uncontrolled production of reactive oxygen species (ROS) results in oxidative stress, which does not follow a correct antioxidant response and consequently damages the biological macromolecules such as nucleic acids, proteins, and lipids (Adler et al, 1999;Auten and Davis, 2009;Maltepe and Saugstad, 2009;Linder, 2012 intake, distribution, utilization, and excretion are precisely regulated (Rosenzweig and O'Halloran, 2000;Kim et al, 2008;de Feo et al, 2009;Banci et al, 2010;Festa and Thiele, 2011;Haas et al, 2011).…”

Human superoxide dismutase 1 (hSOD1) maturation through interaction with human copper chaperone for SOD1 (hCCS)

“…The crystal structure of a heterodimeric complex, where an intermolecular disulfide bond links Cys-57 of an inactive mutant of ySOD1 and Cys-229 (Cys-244 in hCCS) of yCCS D3, has been solved (37). It has been proposed that the CCS-dependent SOD1 maturation process involves the interaction of CCS with the reduced disulfide, zincbound form of SOD1 protein, leading to the formation of the dimeric Cu,Zn-SOD1 protein, in a process requiring oxygen (29,38).…”