MOLECULAR BASIS FOR MEMBRANE TRANSPORTERS IN REDOX HOMEOSTASIS: A BIOCHEMICAL AND BIOPHYSICAL APPROACH ON TRANSPORTER-LIGAND INTERACTIONS

Abstract

Membrane transporters have long been recognized for their important role in promoting cell survival through importing nutrients for growth and development as well as exporting stress inducing toxins. Particularly, membrane transporters in redox homeostasis are lucrative drug targets for novel chemotherapeutic agents. The human cystine/glutamate antiporter, xCT, is a long sought-after chemotherapeutic target due to its protective mechanism in preventing oxidative stress buildup in cancer cells, leading to rapid cancer development associated with poor patient outcomes. However, the lack of mechanistic insight into the function of xCT has been identified as a significant barrier in the development of targeted chemotherapeutics. Besides drug development, membrane transporters also have significant merits in the bioengineering field to be used for removal of environmental contaminants. Yeast cadmium factor 1, Ycf1, is a major bioremediation target due to its ability to sequester various heavy metals (Cd2+, Hg2+, Pb2+, As3+) that are major environmental pollutants. Moreover, Ycf1 also shares high structural and functional homology with the human multi-drug resistance protein 1, MRP1, and the cystic fibrosis transmembrane conductance regulator, CFTR. Therefore, we used structural information obtained from cryo-EM, technology that won the 2017 Nobel Prize, complemented with functional biochemical assays to provide a molecular basis for substrate recognition mechanism in the human xCT and yeast Ycf1.