Structure, Mechanism, and Regulation of Sodium/Proton Exchangers

Abstract: Sodium/proton exchangers (NHEs) are secondary active transporters that are ubiquitously found in all kingdoms of life. They facilitate the exchange of protons for sodium ions or other inorganic ions across biological membranes, regulating pH, sodium levels, and osmotic pressure. They are therefore involved in many fundamental cellular processes such as cell migration and proliferation, and trafficking and turnover of vesicles. Their dysfunction consequently implicates them in a number of diseases and disorders, including hypertension, heart failure, epilepsy, autism spectrum disorders, and brain cancer, making them potential targets for drug development. It is therefore crucial to clearly establish their structure, the molecular basis of ion translocation and their regulation.In this thesis I discuss the key findings of four publications I contributed to with my research. As part of these findings, we could confirm that sodium/proton exchangers operate according to the now broadly accepted elevator transport mechanism. We identified the residues of the ion-binding site that enable electrogenic ion transport in bacterial sodium/proton antiporters, and how they are potentially linked to adaption to different temperature environments. We provide a structural link between two models of regulation by pH of bacterial NhaA; suggesting a channel-like activation of a secondary active transporter. We determined the structure of endosomal NHE9, the first structure of a mammalian sodium/proton exchanger. The structure shows that these transporters, exemplified here by NHE9, share the same topology, fold, and transport mechanism as was observed in bacterial antiporters. In addition, we showed that NHE9 preferentially binds phosphatidylinositol phosphates, a class of lipids enriched in endosomes and involved in a number of signaling and regulation pathways, suggesting a potential regulatory mechanism for NHE9. Taken together, this research contributes to the growing understanding of sodium/proton exchangers and provides direction for future research.