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.

Fig. 1

Schematic representation of the topology of human Ctr1. Trans-membrane (TM) segments of the same monomer are labeled with the number of the corresponding trans-membrane segments in the sequence (1 = TM1, 2 = TM2, 3 = TM3). The copper-binding MxxxM-motif in TM2 is labeled only in one monomer. Met-rich motif refers to the multiple metal-binding residues present in the N-terminal tail. MPM- and HCH-binding motifs at the N- and C-termini are indicated, respectively

Fig. 2

Schematic representation of the topology of copper(I)-transporting ATP7A and ATP7B in analogy with SERCA. The topological scheme includes the A-domain (PDB 2KIJ), the ATP-bound N-domain (PDB code 2KMV) and each NMBDs (domain1 PDB code 1KVJ; domain2 PDB code 1S6U; domains 3–4 PDB code 2ROP; and domains 5–6 PDB code 2EW9) structures. The structure of the P-domain was modeled using as template the structure of corresponding domain in the homologous protein from A. fulgidus (PDB code 2B8E). The structural arrangement of the eight transmembrane helices is obtained from the cryoelectron microscopy model of CopA from A. fulgidus (PDB code 2VOY). The copper(I)-binding cysteines in both N-terminal domains and transmembrane CPC region are shown as yellow spheres. The predicted position of the residues constituting site II in the transmembrane region are shown as orange spheres

Fig. 3

Proposed mechanism of copper transfer and CCS-dependent activation of Cu,Zn-SOD1^S–S. The crystal structure of the yeast SOD1-yeast CCS heterodimeric complex ([131], PDB code 1JK9) and the structures of dimeric Zn,E-SOD^SH, Cu,Zn-SOD^S-S and monomeric Cu,Zn-SOD^S-S (PDB codes 2AF2, 1L3N and 1BA9, respectively) are shown. CCS domains I, II, III are in magenta, cyan and blue, respectively. Zn(II) and Cu(I) ions are shown as blue and green spheres, respectively. The side chains of cysteines are shown as red sticks

Fig. 4

Proposed mechanism of copper insertion into the Cu_A site of cytochrome c oxidase. The crystal structure of bovine Cox2 (PDB code 2ZXW) and the solution structures of human Mia40, Cox17, Sco1 and Sco2 (PDB codes 2K3J, 2RN9, 2RNB, 2GVP, 2GT6) in their different metal or redox states are shown. Cysteine residues involved in copper binding or disulfide bond formation are shown as yellow sticks. Lys 25 in Cox17 and His copper(I) ligands in Sco1 and Sco2 are shown as blue sticks. Copper ions are shown as magenta spheres. The unknown transporter (L) proposed to be involved in copper availability for apoCox17 in the IMS is shown in red. The TOM complex involved in Cox17 protein import into the IMS is schematically shown