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Publication Abstract from PubMed

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 A 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.

Structure, mechanism and lipid-mediated remodeling of the mammalian Na(+)/H(+) exchanger NHA2.,Matsuoka R, Fudim R, Jung S, Zhang C, Bazzone A, Chatzikyriakidou Y, Robinson CV, Nomura N, Iwata S, Landreh M, Orellana L, Beckstein O, Drew D Nat Struct Mol Biol. 2022 Feb;29(2):108-120. doi: 10.1038/s41594-022-00738-2., Epub 2022 Feb 16. PMID:35173351^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.