Abstract
Zinc is an essential metal to life. This transition metal is a structural component of many proteins and is actively involved in the catalytic activity of cell enzymes. In either case, these zinc-containing proteins are metalloproteins. However, the amino acid residues that serve as ligands for metal coordination are not necessarily the same in structural proteins compared to enzymes. While crystals of structural proteins that bind zinc reveal a higher preference for cysteine sulfhydryls rather than histidine imidazole rings, catalytic enzymes reveal the opposite, i.e., a greater preference for the histidines over cysteines for catalysis, plus the influence of carboxylic acids. Based on this paradigm, we reviewed the putative ligands of zinc in ionotropic receptors, where zinc has been described as an allosteric modulator of channel receptors. Although these receptors do not strictly qualify as metalloproteins since they do not normally bind zinc in structural domains, they do transitorily bind zinc at allosteric sites, modifying transiently the receptor channel’s ion permeability. The present contribution summarizes current information showing that zinc allosteric modulation of receptor channels occurs by the preferential metal coordination to imidazole rings as well as to the sulfhydryl groups of cysteine in addition to the carboxyl group of acid residues, as with enzymes and catalysis. It is remarkable that most channels, either voltage-sensitive or transmitter-gated receptor channels, are susceptible to zinc modulation either as positive or negative regulators.
Highlights
Are ion channels metalloproteins? Some may qualify as such, but most ion channels activated by transmitters or agonists are not essentially metalloproteins, since they do not often contain stably bound metal(s), as occurs with enzymes or structural proteins [1]
While Cys only appears in shells of positive modulation, lysines (Lys) are present only in negative modulation sites. Ligands such as Asp or Gln or Glu have almost identical proportions on either mode of regulation. This analysis was made taking in account the proposed ligands for the modulation of ligand-gated ion channels presented in Table 4, but as reviewed in Section 4, zinc coordination in HV1 channels is composed of two His ligands [89], supporting the view that the zinc ligands in allosteric modulation are similar to those found in catalytic sites of proteins
Our contention that ion channels, agonist-gated receptor channels, may be considered metalloproteins is, in our mind, abundantly supported by the reviewed data, which will certainly be enriched by further experimental support
Summary
Are ion channels metalloproteins? Some may qualify as such, but most ion channels activated by transmitters or agonists are not essentially metalloproteins, since they do not often contain stably bound metal(s), as occurs with enzymes or structural proteins [1]. During the fraction of time that the channel is allosterically modulated, metals coordinate at a specific binding pocket of the receptor channel, changing its conformation and biological properties. This interaction is reversible; an indication that once the metal dissociates from the channel binding site, the native receptor conformation is recreated and susceptible to a subsequent allosteric regulation. Several recent research papers and revisions [5,6,7,8,9,10] have authoritatively addressed the relevance of Zn(II) in structural proteins as well as its role in enzyme catalysis, but to date, no review has addressed in depth the role of zinc as an ion channel regulator
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