Metal transport across biomembranes: emerging models for a distinct chemistry

Abstract

Transition metals are essential components of important biomolecules, and their homeostasis is central to many life processes. Transmembrane transporters are key elements controlling the distribution of metals in various compartments. However, due to their chemical properties, transition elements require transporters with different structural-functional characteristics from those of alkali and alkali earth ions. Emerging structural information and functional studies have revealed distinctive features of metal transport. Among these are the relevance of multifaceted events involving metal transfer among participating proteins, the importance of coordination geometry at transmembrane transport sites, and the presence of the largely irreversible steps associated with vectorial transport. Here, we discuss how these characteristics shape novel transition metal ion transport models.

FIGURE 1.

Structures and metal-binding sites of metal transporters. A, structure of the Cu⁺-ATPase CopA (Protein Data Bank code 3RFU), with amino acids forming the two transmembrane Cu⁺-binding sites indicated in red. B, CusABC model assembled with Swiss-PDBViewer using the CusAB (code 3NE5) and CusC (code 3PIK) structures. The magnified section indicates the Cu⁺-binding sites (red) in a CusA monomer. C, side and apical views of modeled Ctr transporters (provided by Dr. Vincent Unger, Northwestern University). Extracytoplasmic and transmembrane Met-rich Cu⁺-binding sites are indicated in red. Darker helices correspond to those involved in transmembrane metal binding. D, structure of the CDF transporter YiiP (code 2QFI). Red amino acids indicate Zn²⁺-binding sites. Dotted areas indicate the three metal-binding sites in each YiiP monomer.

FIGURE 2.

Catalytic cycle of a Cu⁺-ATPase. Cu⁺ binding to two TM-MBSs is required for catalytic phosphorylation by ATP (E₁∼P·Cu₂⁺). Note the irreversibility of Cu⁺ transfer from the chaperone (CopZ) to the transport site and that full occupancy is reached only in the presence of ATP. Metal is released after a conformational change (to E₂∼P) leading TM-MBSs to open to the vesicular/extracellular medium. E₂ → E₁ transition is accelerated by ATP (or ADP) acting in a modulatory mode (low affinity). See Ref. for more details.

FIGURE 3.

Cu⁺ chaperone/Cu⁺-ATPase interaction. A, docking was modeled using ClusPro (83). A. fulgidus CopA (green) was modeled after L. pneumophila CopA (Protein Data Bank code 3RFU), whereas the model of the C-terminal domain of A. fulgidus CopZ (ochre) was built using Enterococcus hirae CopZ (code 1CPZ) as a template. The CopA platform for interaction with CopZ is shown in blue. B, surface charges in the predicted docking of CopZ with CopA. Positive and negative charge densities are indicated in blue and red, respectively.