Structure and function of H+/K+ pump mutants reveal Na+/K+ pump mechanisms

Victoria C. Young, Hanayo Nakanishi, Dylan J. Meyer, Tomohiro Nishizawa, Atsunori Oshima, Pablo Artigas () and Kazuhiro Abe ()
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Victoria C. Young: Texas Tech University Health Sciences Center
Hanayo Nakanishi: Nagoya University
Dylan J. Meyer: Texas Tech University Health Sciences Center
Tomohiro Nishizawa: Yokohama City University, Tsurumi
Atsunori Oshima: Nagoya University
Pablo Artigas: Texas Tech University Health Sciences Center
Kazuhiro Abe: Nagoya University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Ion-transport mechanisms evolve by changing ion-selectivity, such as switching from Na+ to H+ selectivity in secondary-active transporters or P-type-ATPases. Here we study primary-active transport via P-type ATPases using functional and structural analyses to demonstrate that four simultaneous residue substitutions transform the non-gastric H+/K+ pump, a strict H+-dependent electroneutral P-type ATPase, into a bona fide Na+-dependent electrogenic Na+/K+ pump. Conversion of a H+-dependent primary-active transporter into a Na+-dependent one provides a prototype for similar studies of ion-transport proteins. Moreover, we solve the structures of the wild-type non-gastric H+/K+ pump, a suitable drug target to treat cystic fibrosis, and of its Na+/K+ pump-mimicking mutant in two major conformations, providing insight on how Na+ binding drives a concerted mechanism leading to Na+/K+ pump phosphorylation.

Date: 2022
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DOI: 10.1038/s41467-022-32793-0

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