NhaA: A Unique Structural Fold of Secondary Active Transporters

• Published in: Israel journal of chemistry Vol. 55; no. 11-12; pp. 1233 - 1239
• Main Authors: Padan, Etana, Michel, Hartmut
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.11.2015; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: antiporters; Bacteria; Bacteriology; Binding sites; Cations; Crystal structure; Diseases; Escherichia coli; Exchange; homeostasis; Human; metabolism; protein folding; Sodium
• ISSN: 0021-2148; 1869-5868
• DOI: 10.1002/ijch.201500044

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.