Membrane accessibility of glutathione

Alvaro Garcia, Nasma D Eljack, Marc-Antoine Sani, Frances Separovic, Helge H Rasmussen, Wojciech Kopec, Himanshu Khandelia, Flemming Cornelius, Ronald J Clarke

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Regulation of the ion pumping activity of the Na(+),K(+)-ATPase is crucial to the survival of animal cells. Recent evidence has suggested that the activity of the enzyme could be controlled by glutathionylation of cysteine residue 45 of the β-subunit. Crystal structures so far available indicate that this cysteine is in a transmembrane domain of the protein. Here we have analysed via fluorescence and NMR spectroscopy as well as molecular dynamics simulations whether glutathione is able to penetrate into the interior of a lipid membrane. No evidence for any penetration of glutathione into the membrane was found. Therefore, the most likely mechanism whereby the cysteine residue could become glutathionylated is via a loosening of the α-β subunit association, creating a hydrophilic passageway between them to allow access of glutathione to the cysteine residue. By such a mechanism, glutathionylation of the protein would be expected to anchor the modified cysteine residue in a hydrophilic environment, inhibiting further motion of the β-subunit during the enzyme's catalytic cycle and suppressing enzymatic activity, as has been experimentally observed. The results obtained, therefore, suggest a possible structural mechanism of how the Na(+),K(+)-ATPase could be regulated by glutathione.

Original languageEnglish
JournalBBA Biomembranes
Issue number10, Part A
Pages (from-to)2430–2436
Publication statusPublished - 29. Jul 2015


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