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Cadmium is a highly toxic environmental contaminant, which is implicated in various disorders in all living organisms. While cadmium efflux transporters are known to be vital for cadmium defense in bacteria, the counterparts in eukaryotes, including fungi, plant, fish, and mammals remain to be characterized.<P> The long-term goals of this project are the elucidation of molecular mechanisms of cadmium detoxification in eukaryotes and employing these mechanistic insights for the reduction of cadmium intake of humans. <P>This proposal focuses on a cadmium exporter that we recently identified in baker's yeast. We will characterize function and define a mechanism by which cells can control expression of this transporter in accordance with sensing of cellular cadmium. Given that most components for metal metabolism are conserved in eukaryotes, our studies using a yeast model would facilitate mechanistic insights into metal detoxification in plants, animals and humans. <P>The proposed study also underpins a potential biotechnological application of the cadmium exporter to reduce cadmium contents in plants as a tool for limiting human consumption. <P>Collectively, the outcomes of characterization of a new cadmium exporter, ultimately facilitate development of methods for the prevention of cadmium exposure, treatment of cadmium related diseases, and efficient remediation of cadmium from the environment.
Non-Technical Summary: Cadmium is a highly toxic environmental contaminant that is widespread and known to be implicated in a number of human disorders, including kidney disease, cancer, and endocrine disruption. Given that diet and smoking are major sources of cadmium, agricultural products (both plant and animal origin) largely determines human exposure of cadmium. Mechanistic insights into cellular cadmium uptake, sequestration and extrusion would facilitate prevention and treatment of cadmium related disorders and the development of methods to minimize cadmium accumulation in food chain. The long-term goals of this project are the characterization of molecular mechanisms of cadmium detoxification and employing this knowledge to reduce cadmium exposure to humans. During the search for genes involved in metal resistance in baker's yeast, a model eukaryote, we have identified a novel cadmium exporter that plays a critical role for cadmium detoxification. This application focuses on characterization of the function, mechanisms of action and regulation of this recently identified cadmium transporter. The central hypothesis of this study is that the transporter is the first cadmium selective efflux pump that is unique in structure, metal specificity and mode of regulation. This will be tested using biophysical, biochemical, cell biological and genetic approaches. This research will ultimately advance our ability to combat cadmium related disorders in humans. <P> Approach: This project employs a combination of biophysical, biochemical, cell biological and genetic approaches. First, metal specificity of the transporter will be elucidated, and structural determinants of the specificity will be identified. This study will largely focus on metal transport assays and structure function analysis of predicted metal binding domains and residues. Second, a multidisciplinary approach combining genetics and cell biology will characterize how yeast senses cadmium to control expression levels of this cadmium efflux pump.