Structural analysis of the Na+/H+ exchanger isoform 1 (NHE1) using the divide and conquer approach

The sodium/proton exchanger isoform 1 (NHE1) is an ubiquitous plasma membrane protein that regulates intracellular pH by removing excess intracellular acid. NHE1 is important in heart disease and cancer, making it an attractive therapeutic target. Although much is known about the function of NHE1, current structural knowledge of NHE1 is limited to two conflicting topology models: a low-resolution molecular envelope from electron microscopy, and comparison with a crystal structure of a bacterial homologue, NhaA. Our laboratory has used high-resolution nuclear magnetic resonance (NMR) spectroscopy to investigate the structures of individual transmembrane helices of NHE1 - a divide and conquer approach to the study of this membrane protein. In this review, we discuss the structural and functional insights obtained from this approach in combination with functional data obtained from mutagenesis experiments on the protein. We also compare the known structure of NHE1 transmembrane segments with the structural and functional insights obtained from a bacterial sodium/proton exchanger homologue, NhaA. The structures of regions of the NHE1 protein that have been determined have both similarities and specific differences to the crystal structure of the NhaA protein. These have allowed insights into both the topology and the function of the NHE1 protein.