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Selective binding of a toxin and phosphatidylinositides to a mammalian potassium channel
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 P...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430785/ https://www.ncbi.nlm.nih.gov/pubmed/30902995 http://dx.doi.org/10.1038/s41467-019-09333-4 |
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author | Liu, Yang LoCaste, Catherine E. Liu, Wen Poltash, Michael L. Russell, David H. Laganowsky, Arthur |
author_facet | Liu, Yang LoCaste, Catherine E. Liu, Wen Poltash, Michael L. Russell, David H. Laganowsky, Arthur |
author_sort | Liu, Yang |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6430785 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-64307852019-03-25 Selective binding of a toxin and phosphatidylinositides to a mammalian potassium channel Liu, Yang LoCaste, Catherine E. Liu, Wen Poltash, Michael L. Russell, David H. Laganowsky, Arthur Nat Commun Article 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. Nature Publishing Group UK 2019-03-22 /pmc/articles/PMC6430785/ /pubmed/30902995 http://dx.doi.org/10.1038/s41467-019-09333-4 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Liu, Yang LoCaste, Catherine E. Liu, Wen Poltash, Michael L. Russell, David H. Laganowsky, Arthur Selective binding of a toxin and phosphatidylinositides to a mammalian potassium channel |
title | Selective binding of a toxin and phosphatidylinositides to a mammalian potassium channel |
title_full | Selective binding of a toxin and phosphatidylinositides to a mammalian potassium channel |
title_fullStr | Selective binding of a toxin and phosphatidylinositides to a mammalian potassium channel |
title_full_unstemmed | Selective binding of a toxin and phosphatidylinositides to a mammalian potassium channel |
title_short | Selective binding of a toxin and phosphatidylinositides to a mammalian potassium channel |
title_sort | selective binding of a toxin and phosphatidylinositides to a mammalian potassium channel |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430785/ https://www.ncbi.nlm.nih.gov/pubmed/30902995 http://dx.doi.org/10.1038/s41467-019-09333-4 |
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