Tryptophan Scanning Analysis of the Membrane Domain of CTR-Copper Transporters

Membrane proteins of the CTR family mediate cellular copper uptake in all eukaryotic cells and have been shown to participate in uptake of platinum-based anticancer drugs. Despite their importance for life and the clinical treatment of malignancies, directed biochemical studies of CTR proteins have been difficult because high-resolution structural information is missing. Building on our recent 7Å structure of the human copper transporter hCTR1, we present the results of an extensive tryptophan-scanning analysis of hCTR1 and its distant relative, yeast CTR3. The comparative analysis supports our previous assignment of the transmembrane helices and shows that most functionally and structurally important residues are clustered around the threefold axis of CTR trimers or engage in helix packing interactions. The scan also identified residues that may play roles in interactions between CTR trimers and suggested that the first transmembrane helix serves as an adaptor that allows evolutionarily diverse CTRs to adopt the same overall structure. Together with previous biochemical and biophysical data, the results of the tryptophan scan are consistent with a mechanistic model in which copper transport occurs along the center of the trimer

Pregabalin antagonizes copper-induced toxicity in the brain: in vitro and in vivo studies.

Copper plays key roles in brain metabolism. Disorders of copper metabolism impact on neural signaling. The intracellular and extracellular concentrations of copper are tightly regulated. Pregabalin is a drug with multiple modes of action and has a high-affinity binding site for the alpha2delta subunit of voltage-gated calcium channels.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Modelling Inborn Errors of Metabolism in Zebrafish

The majority of human inborn errors of metabolism are fatal multisystem disorders that lack proper treatment and have a poorly understood mechanistic basis. Novel technologies are required to address this issue, and the use of zebrafish to model these diseases is an emerging field. Here we present the published zebrafish models of inborn metabolic diseases, discuss their validity, and review the novel mechanistic insights that they have provided. We also review the available methods for creating and studying zebrafish disease models, advantages and disadvantages of using this model organism, and successful examples of the use of zebrafish for drug discovery and development. Using a zebrafish to model inborn errors of metabolism in vivo, although still in its infancy, shows promise for a deeper understanding of disease pathomechanisms, onset, and progression, and also for the development of specific therapies