Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation
The function of the voltage-gated KCNQ1 potassium channel is regulated by co-assembly with KCNE auxiliary subunits. KCNQ1-KCNE1 channels generate the slow delayed rectifier current, IKs, which contributes to the repolarization phase of the cardiac action potential. A three amino acid motif (F57-T58-...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/57680 |
| _version_ | 1811180323605577728 |
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| author | Georg Kuenze Carlos G Vanoye Reshma R Desai Sneha Adusumilli Kathryn R Brewer Hope Woods Eli F McDonald Charles R Sanders Alfred L George Jr Jens Meiler |
| author_facet | Georg Kuenze Carlos G Vanoye Reshma R Desai Sneha Adusumilli Kathryn R Brewer Hope Woods Eli F McDonald Charles R Sanders Alfred L George Jr Jens Meiler |
| author_sort | Georg Kuenze |
| collection | DOAJ |
| description | The function of the voltage-gated KCNQ1 potassium channel is regulated by co-assembly with KCNE auxiliary subunits. KCNQ1-KCNE1 channels generate the slow delayed rectifier current, IKs, which contributes to the repolarization phase of the cardiac action potential. A three amino acid motif (F57-T58-L59, FTL) in KCNE1 is essential for slow activation of KCNQ1-KCNE1 channels. However, how this motif interacts with KCNQ1 to control its function is unknown. Combining computational modeling with electrophysiological studies, we developed structural models of the KCNQ1-KCNE1 complex that suggest how KCNE1 controls KCNQ1 activation. The FTL motif binds at a cleft between the voltage-sensing and pore domains and appears to affect the channel gate by an allosteric mechanism. Comparison with the KCNQ1-KCNE3 channel structure suggests a common transmembrane-binding mode for different KCNEs and illuminates how specific differences in the interaction of their triplet motifs determine the profound differences in KCNQ1 functional modulation by KCNE1 versus KCNE3. |
| first_indexed | 2024-04-11T09:01:06Z |
| format | Article |
| id | doaj.art-eb5503437d7d4717b295c6786fb43fec |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:01:06Z |
| publishDate | 2020-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-eb5503437d7d4717b295c6786fb43fec2022-12-22T04:32:48ZengeLife Sciences Publications LtdeLife2050-084X2020-10-01910.7554/eLife.57680Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activationGeorg Kuenze0https://orcid.org/0000-0003-1799-346XCarlos G Vanoye1Reshma R Desai2Sneha Adusumilli3Kathryn R Brewer4Hope Woods5Eli F McDonald6https://orcid.org/0000-0002-0572-330XCharles R Sanders7https://orcid.org/0000-0003-2046-2862Alfred L George Jr8Jens Meiler9Center for Structural Biology, Vanderbilt University, Nashville, United States; Department of Chemistry, Vanderbilt University, Nashville, United States; Institute for Drug Discovery, Leipzig University, Leipzig, GermanyDepartment of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United StatesDepartment of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United StatesDepartment of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United StatesCenter for Structural Biology, Vanderbilt University, Nashville, United States; Department of Biochemistry, Vanderbilt University, Nashville, United StatesCenter for Structural Biology, Vanderbilt University, Nashville, United States; Department of Chemistry, Vanderbilt University, Nashville, United StatesCenter for Structural Biology, Vanderbilt University, Nashville, United States; Department of Chemistry, Vanderbilt University, Nashville, United StatesCenter for Structural Biology, Vanderbilt University, Nashville, United States; Department of Biochemistry, Vanderbilt University, Nashville, United StatesDepartment of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United StatesCenter for Structural Biology, Vanderbilt University, Nashville, United States; Department of Chemistry, Vanderbilt University, Nashville, United States; Institute for Drug Discovery, Leipzig University, Leipzig, Germany; Department of Pharmacology, Vanderbilt University, Nashville, United StatesThe function of the voltage-gated KCNQ1 potassium channel is regulated by co-assembly with KCNE auxiliary subunits. KCNQ1-KCNE1 channels generate the slow delayed rectifier current, IKs, which contributes to the repolarization phase of the cardiac action potential. A three amino acid motif (F57-T58-L59, FTL) in KCNE1 is essential for slow activation of KCNQ1-KCNE1 channels. However, how this motif interacts with KCNQ1 to control its function is unknown. Combining computational modeling with electrophysiological studies, we developed structural models of the KCNQ1-KCNE1 complex that suggest how KCNE1 controls KCNQ1 activation. The FTL motif binds at a cleft between the voltage-sensing and pore domains and appears to affect the channel gate by an allosteric mechanism. Comparison with the KCNQ1-KCNE3 channel structure suggests a common transmembrane-binding mode for different KCNEs and illuminates how specific differences in the interaction of their triplet motifs determine the profound differences in KCNQ1 functional modulation by KCNE1 versus KCNE3.https://elifesciences.org/articles/57680KCNQ1KCNE1long QT syndromevoltage-gated potassium ion channelRosettamolecular dynamics simulation |
| spellingShingle | Georg Kuenze Carlos G Vanoye Reshma R Desai Sneha Adusumilli Kathryn R Brewer Hope Woods Eli F McDonald Charles R Sanders Alfred L George Jr Jens Meiler Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation eLife KCNQ1 KCNE1 long QT syndrome voltage-gated potassium ion channel Rosetta molecular dynamics simulation |
| title | Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation |
| title_full | Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation |
| title_fullStr | Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation |
| title_full_unstemmed | Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation |
| title_short | Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation |
| title_sort | allosteric mechanism for kcne1 modulation of kcnq1 potassium channel activation |
| topic | KCNQ1 KCNE1 long QT syndrome voltage-gated potassium ion channel Rosetta molecular dynamics simulation |
| url | https://elifesciences.org/articles/57680 |
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