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.Micronutrient transition metals (manganese, iron, cobalt, nickel, copper, zinc, molybdenum, and tungsten) serve catalytic and structural functions as prosthetic groups in metalloproteins. In these roles, they are required for a number of diverse physiological processes, ranging from gene transcription to respiration (1). However, despite their essential roles and ubiquitous presence, metals can cause deleterious effects by catalyzing the production of free radicals or by simply impairing metalloenzyme functions by substituting for the optimal metal cofactors. Consequently, organisms strive to maintain a tightly controlled homeostasis of these elements through the coordinated action of transmembrane transporters; chaperone, sequestering, and storage molecules; and metal-responsive transcriptional regulators (2-4). These components distribute the ions to appropriate targets and maintain adequate metal quotas, keeping the cellular compartments essentially free of unsequestered metals (3,5,6).This minireview focuses on the structural and functional aspects of transmembrane transporters that participate in the homeostasis of transition metals. The current understanding of ion transmembrane transport is rooted in 6 decades of research characterizing alkali (H ϩ , Na ϩ , and K ϩ ) and alkali earth (Mg 2ϩ and Ca 2ϩ ) channels, carriers, and pumps. These ions are free (hydrated) and abundant in biological systems. Therefore, their transport mechanisms are shaped by electrochemical gradients and governed by their reversible interaction with transmembrane transport sites constituted by polar amino acid side chains (7). Consideration of the physicochemical differences between alkali/alkali earth and transition metal ions quickly reveals that the existing models describing ion transmembrane translocation cannot explain the mechanism of transport of transition metals. In this context, emerging paradigms for the transport of uncomplexed metal ions are discussed here. Transporters of metal complexes (siderophore-metal, heme, etc.) will not be considered because their selectivity and mechanism might not be determined by the bound metal, but rather by the co...

The Mechanism of Cu+ Transport ATPases

“…Interestingly, these data are in agreement with previous bioinformatic analysis showing that the electrostatic docking of these proteins relies in a specific interaction between the E190/E193/E205/D145 region of CtCopZ (Fig. 4A) and the electropositive platform of CopA (11).…”

“…These residues were alanine-substituted, creating three different proteins used in this study. A, Ct-CopZ M1 putative Ct-CopZ electronegative exposed surface facing toward the platform of AfCopA (11). B, Ct-CopZ M2 electronegative surface.…”

“…The Archaeoglobus fulgidus CopA-CopZ provides a framework to test these ideas, because this Cu ϩ -ATPase (AfCopA) and its corresponding Cu ϩ chaperone (AfCopZ) have served as models for previous mechanistic studies (11,15,16,18,34). The description of their interaction provided a basis for our current understanding of Cu ϩ access to transmembrane transporters (10,24).…”

“…This interaction would allow Cu ϩ ligating groups in the ATPase to substitute those in the chaperone, enabling Cu ϩ transfer via ligand exchange. Implicit in this model was the specific recognition of the interacting proteins contributing to the enzyme selectivity mechanism and to constant metal sequestration (11,15).…”

Fine-tuning of Substrate Affinity Leads to Alternative Roles of Mycobacterium tuberculosis Fe2+-ATPases

“…The specificity of their transmembrane metal binding sites (TM-MBSs) 2 is determined by invariant amino acid sequences in their last three transmembrane segments (TMs) (17, 19, 24 -26). However, activation by non-cognate substrates has been reported for most P 1B -ATPase subgroups (22,27 …”