NhaA: A Unique Structural Fold of Secondary Active Transporters

The Na+/H+ antiporters transport sodium (or several other monovalent cations) in exchange for H+ across lipid bilayers in all kingdoms of life. They are critical in the pH homeostasis of cytoplasm and/or organelles. In humans, these proteins are associated with the pathophysiology of various diseases. Yet, the most extensively studied Na+/H+ antiporter is Ec-NhaA, the main Na+/H+ antiporter of Escherichia coli. The crystal structure of an inactive, down-regulated Ec-NhaA, determined at acidic pH, has provided the first structural insights into the antiport mechanism and pH regulation of an Na+/H+ antiporter. It reveals a unique structural fold (called the NhaA fold) in which helical transmembrane segments (TMs) are organized in inverted-topology repeats, including two antiparallel non-helical extended chain regions that cross each other, forming a delicate electrostatic balance in the middle of the membrane. The NhaA fold contributes to the cation binding site and facilitates rapid conformational changes of Ec-NhaA. The NhaA fold has now been recognized to be shared by four Na+/H+ antiporters (bacterial and archaeal) and two Na+ symporters. Thus far, no crystal structure of any of the human Na+/H+ antiporters has been determined. Nevertheless, the Ec-NhaA crystal structure has enabled the structural modeling of NHE1, NHE9, and NHA2, which are involved in human pathophysiology. Future elucidation of structure-function relationships of eukaryotic and prokaryotic Na+/H+ antiporters are likely to provide insights into the human pathophysiology. Here, we will focus on the NhaA structural fold which underpins the antiporter functionality of Ec-NhaA and the secondary active transporters.