Mechanistic Insights into Na+-dependent HCO3- Transport by NBCn2 (SLC4A10)

Abstract

The 3D structure and mechanism of action are unknown for the integral plasma membrane transport protein Solute Carrier 4A10, which has been characterized functionally as an electroneutral Na+:HCO3- cotransporter. We used structure prediction and molecular dynamics simulations to study the binding of the transported ions to the Solute Carrier 4A10 protein and suggest a model of sequential binding of Na+ followed by HCO3- to the ion binding domain. The binding of HCO3- to the protein appears to depend absolutely on Na+ binding. Conversely, binding of HCO3- stabilizes the interaction between Na+ and its binding site. This allows the subsequent conformational changes of the Solute Carrier 4A10 protein and, thus, ion translocation. Measurements of intracellular pH and Na+ concentration revealed the dependence of Na+ on HCO3- transport. The study lays the necessary foundation for advanced analysis of ion translocation and the development of selective transport inhibitors of Solute Carrier 4A10 and other proteins of the protein family of HCO3- transporters.