Structure, mechanism and lipid-mediated remodeling of the mammalian Na+/H+exchanger NHA2

Autor: Matsuoka, Rei, Fudim, Roman, Jung, Sukkyeong, Zhang, Chenou, Bazzone, Andre, Chatzikyriakidou, Yurie, Robinson, Carol V., Nomura, Norimichi, Iwata, So, Landreh, Michael, Orellana, Laura, Beckstein, Oliver, Drew, David
Zdroj: Nature Structural and Molecular Biology; February 2022, Vol. 29 Issue: 2 p108-120, 13p
Abstrakt: The Na+/H+exchanger SLC9B2, also known as NHA2, correlates with the long-sought-after Na+/Li+exchanger linked to the pathogenesis of diabetes mellitus and essential hypertension in humans. Despite the functional importance of NHA2, structural information and the molecular basis for its ion-exchange mechanism have been lacking. Here we report the cryo-EM structures of bison NHA2 in detergent and in nanodiscs, at 3.0 and 3.5 Å resolution, respectively. The bison NHA2 structure, together with solid-state membrane-based electrophysiology, establishes the molecular basis for electroneutral ion exchange. NHA2 consists of 14 transmembrane (TM) segments, rather than the 13 TMs previously observed in mammalian Na+/H+exchangers (NHEs) and related bacterial antiporters. The additional N-terminal helix in NHA2 forms a unique homodimer interface with a large intracellular gap between the protomers, which closes in the presence of phosphoinositol lipids. We propose that the additional N-terminal helix has evolved as a lipid-mediated remodeling switch for the regulation of NHA2 activity.
Databáze: Supplemental Index
Externí odkaz: