Molecular Events behind the Selectivity and Inactivation Properties of Model NaK-Derived Ion Channels
Y55W mutants of non-selective NaK and partly K<sup>+</sup>-selective NaK2K channels have been used to explore the conformational dynamics at the pore region of these channels as they interact with either Na<sup>+</sup> or K<sup>+</sup>. A major conclusion is that...
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MDPI AG
2022-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/16/9246 |
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| author | Ana Marcela Giudici María Lourdes Renart Ana Coutinho Andrés Morales José Manuel González-Ros José Antonio Poveda |
| author_facet | Ana Marcela Giudici María Lourdes Renart Ana Coutinho Andrés Morales José Manuel González-Ros José Antonio Poveda |
| author_sort | Ana Marcela Giudici |
| collection | DOAJ |
| description | Y55W mutants of non-selective NaK and partly K<sup>+</sup>-selective NaK2K channels have been used to explore the conformational dynamics at the pore region of these channels as they interact with either Na<sup>+</sup> or K<sup>+</sup>. A major conclusion is that these channels exhibit a remarkable pore conformational flexibility. Homo-FRET measurements reveal a large change in W55–W55 intersubunit distances, enabling the selectivity filter (SF) to admit different species, thus, favoring poor or no selectivity. Depending on the cation, these channels exhibit wide-open conformations of the SF in Na<sup>+</sup>, or tight induced-fit conformations in K<sup>+</sup>, most favored in the four binding sites containing NaK2K channels. Such conformational flexibility seems to arise from an altered pattern of restricting interactions between the SF and the protein scaffold behind it. Additionally, binding experiments provide clues to explain such poor selectivity. Compared to the K<sup>+</sup>-selective KcsA channel, these channels lack a high affinity K<sup>+</sup> binding component and do not collapse in Na<sup>+</sup>. Thus, they cannot properly select K<sup>+</sup> over competing cations, nor reject Na<sup>+</sup> by collapsing, as K<sup>+</sup>-selective channels do. Finally, these channels do not show C-type inactivation, likely because their submillimolar K<sup>+</sup> binding affinities prevent an efficient K<sup>+</sup> loss from their SF, thus favoring permanently open channel states. |
| first_indexed | 2024-03-09T13:16:19Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T13:16:19Z |
| publishDate | 2022-08-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-4db73d378a844da6839f0f452d3c4f842023-11-30T21:35:14ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-08-012316924610.3390/ijms23169246Molecular Events behind the Selectivity and Inactivation Properties of Model NaK-Derived Ion ChannelsAna Marcela Giudici0María Lourdes Renart1Ana Coutinho2Andrés Morales3José Manuel González-Ros4José Antonio Poveda5Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), and Instituto de Biología Molecular y Celular (IBMC), Universidad Miguel Hernández, 03202 Elche, SpainInstituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), and Instituto de Biología Molecular y Celular (IBMC), Universidad Miguel Hernández, 03202 Elche, SpainiBB-Institute for Bioengineering and Bioscience, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, PortugalDepartamento de Fisiología, Genética y Microbiología, Universidad de Alicante, 03080 Alicante, SpainInstituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), and Instituto de Biología Molecular y Celular (IBMC), Universidad Miguel Hernández, 03202 Elche, SpainInstituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), and Instituto de Biología Molecular y Celular (IBMC), Universidad Miguel Hernández, 03202 Elche, SpainY55W mutants of non-selective NaK and partly K<sup>+</sup>-selective NaK2K channels have been used to explore the conformational dynamics at the pore region of these channels as they interact with either Na<sup>+</sup> or K<sup>+</sup>. A major conclusion is that these channels exhibit a remarkable pore conformational flexibility. Homo-FRET measurements reveal a large change in W55–W55 intersubunit distances, enabling the selectivity filter (SF) to admit different species, thus, favoring poor or no selectivity. Depending on the cation, these channels exhibit wide-open conformations of the SF in Na<sup>+</sup>, or tight induced-fit conformations in K<sup>+</sup>, most favored in the four binding sites containing NaK2K channels. Such conformational flexibility seems to arise from an altered pattern of restricting interactions between the SF and the protein scaffold behind it. Additionally, binding experiments provide clues to explain such poor selectivity. Compared to the K<sup>+</sup>-selective KcsA channel, these channels lack a high affinity K<sup>+</sup> binding component and do not collapse in Na<sup>+</sup>. Thus, they cannot properly select K<sup>+</sup> over competing cations, nor reject Na<sup>+</sup> by collapsing, as K<sup>+</sup>-selective channels do. Finally, these channels do not show C-type inactivation, likely because their submillimolar K<sup>+</sup> binding affinities prevent an efficient K<sup>+</sup> loss from their SF, thus favoring permanently open channel states.https://www.mdpi.com/1422-0067/23/16/9246potassium channelsselectivityinactivationconformational flexibilityion bindingthermal stability |
| spellingShingle | Ana Marcela Giudici María Lourdes Renart Ana Coutinho Andrés Morales José Manuel González-Ros José Antonio Poveda Molecular Events behind the Selectivity and Inactivation Properties of Model NaK-Derived Ion Channels International Journal of Molecular Sciences potassium channels selectivity inactivation conformational flexibility ion binding thermal stability |
| title | Molecular Events behind the Selectivity and Inactivation Properties of Model NaK-Derived Ion Channels |
| title_full | Molecular Events behind the Selectivity and Inactivation Properties of Model NaK-Derived Ion Channels |
| title_fullStr | Molecular Events behind the Selectivity and Inactivation Properties of Model NaK-Derived Ion Channels |
| title_full_unstemmed | Molecular Events behind the Selectivity and Inactivation Properties of Model NaK-Derived Ion Channels |
| title_short | Molecular Events behind the Selectivity and Inactivation Properties of Model NaK-Derived Ion Channels |
| title_sort | molecular events behind the selectivity and inactivation properties of model nak derived ion channels |
| topic | potassium channels selectivity inactivation conformational flexibility ion binding thermal stability |
| url | https://www.mdpi.com/1422-0067/23/16/9246 |
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