Hoxhaj G, Najafov A, Toth R, Campbell DG, Prescott AR, Mackintosh C

Here we describe a phosphorylation-based reverse myristoyl switch for mammalian ZNRF2, and show that this E3 ubiquitin ligase and its sister ZNRF1 regulate the sodium/potassium pump (Na(+)/K(+)ATPase). N-myristoylation targets ZNRF1 and ZNRF2 to intracellular membranes and enhances their activity. However, when ZNRF2 is phosphorylated in response to agonists including insulin ...

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and growth factors, it binds to 14-3-3 and is released into the cytosol. On membranes, ZNRF1 and ZNRF2 interact with the Na(+)/K(+)ATPase α1 subunit via their UBZ domains, while their RING domains interact with E2 proteins, predominantly Ubc13 that with Uev1a specifies formation of Lys63-ubiquitin linkages. ZNRF1 and ZNRF2 can ubiquitylate the nucleotide-binding/phosphorylation region of Na(+)/K(+)ATPase α1. Ouabain, a Na(+)/K(+)ATPase inhibitor and therapeutic cardiac glycoside, decreases ZNRF1 protein levels, while knockdown of ZNRF2 inhibits the ouabain-induced decrease of cell surface and total Na(+)/K(+)ATPase α1 levels. Thus, ZNRF1 and ZNRF2 are new players in regulation of the ubiquitous sodium/potassium pump that is tuned to changing demands in many physiological contexts.

Date: Jul. 13, 2012

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