Journal Article

Selective binding of a toxin and phosphatidylinositides to a mammalian potassium channel

Liu, Yang, Laganowsky, Arthur, LoCaste, Catherine E., Poltash, Michael L., Liu, Wen, Russell, David H.

2019

Overview

G-protein-gated inward rectifying potassium channels (GIRKs) require G βγ subunits and phosphorylated phosphatidylinositides (PIPs) for gating. Although studies have provided insight into these interactions, the mechanism of how these events are modulated by G βγ and the binding affinity between PIPs and GIRKs remains poorly understood. Here, native ion mobility mass spectrometry is employed to directly monitor small molecule binding events to mouse GIRK2. GIRK2 binds the toxin tertiapin Q and PIPs selectively and with significantly higher affinity than other phospholipids. A mutation in GIRK2 that causes a rotation in the cytoplasmic domain, similarly to G βγ -binding to the wild-type channel, revealed differences in the selectivity towards PIPs. More specifically, PIP isoforms known to weakly activate GIRKs have decreased binding affinity. Taken together, our results reveal selective small molecule binding and uncover a mechanism by which rotation of the cytoplasmic domain can modulate GIRK•PIP interactions. G-protein-gated inward rectifying potassium channels (GIRKs) require G βγ subunits and phosphorylated phosphatidylinositides (PIPs) for gating. Here authors use native ion mobility mass spectrometry to monitor small molecule binding events to GIRK2 and shed light on the selectivity of GIRK2 towards PIPs.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/58 / 631/45/269 / 631/57 / 82/80 / 82/83 / Affinity / Animals / Bee Venoms - metabolism / Channel gating / G Protein-Coupled Inwardly-Rectifying Potassium Channels - metabolism / Humanities and Social Sciences / Ionic mobility / Ions / Isoforms / Mammals - metabolism / Mass Spectrometry / Mass spectroscopy / Mice / multidisciplinary / Mutation / Mutation - genetics / Phosphatidylinositol / Phosphatidylinositols - metabolism / Phospholipids / Phosphorylation / Potassium / Potassium channels / Potassium channels (inwardly-rectifying) / Protein Binding / Proteins / Rotation / Science / Science (multidisciplinary) / Selective binding / Selectivity / Toxins