Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxin
Venom toxins are invaluable tools for exploring the structure and mechanisms of ion channels. Here, we solve the structure of double-knot toxin (DkTx), a tarantula toxin that activates the heat-activated TRPV1 channel. We also provide improved structures of TRPV1 with and without the toxin bound, an...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/11273 |
| _version_ | 1811180510434557952 |
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| author | Chanhyung Bae Claudio Anselmi Jeet Kalia Andres Jara-Oseguera Charles D Schwieters Dmitriy Krepkiy Chul Won Lee Eun-Hee Kim Jae Il Kim José D Faraldo-Gómez Kenton J Swartz |
| author_facet | Chanhyung Bae Claudio Anselmi Jeet Kalia Andres Jara-Oseguera Charles D Schwieters Dmitriy Krepkiy Chul Won Lee Eun-Hee Kim Jae Il Kim José D Faraldo-Gómez Kenton J Swartz |
| author_sort | Chanhyung Bae |
| collection | DOAJ |
| description | Venom toxins are invaluable tools for exploring the structure and mechanisms of ion channels. Here, we solve the structure of double-knot toxin (DkTx), a tarantula toxin that activates the heat-activated TRPV1 channel. We also provide improved structures of TRPV1 with and without the toxin bound, and investigate the interactions of DkTx with the channel and membranes. We find that DkTx binds to the outer edge of the external pore of TRPV1 in a counterclockwise configuration, using a limited protein-protein interface and inserting hydrophobic residues into the bilayer. We also show that DkTx partitions naturally into membranes, with the two lobes exhibiting opposing energetics for membrane partitioning and channel activation. Finally, we find that the toxin disrupts a cluster of hydrophobic residues behind the selectivity filter that are critical for channel activation. Collectively, our findings reveal a novel mode of toxin-channel recognition that has important implications for the mechanism of thermosensation. |
| first_indexed | 2024-04-11T09:03:24Z |
| format | Article |
| id | doaj.art-fac010dbb26b4b76a28d620e4e754567 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:03:24Z |
| publishDate | 2016-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-fac010dbb26b4b76a28d620e4e7545672022-12-22T04:32:42ZengeLife Sciences Publications LtdeLife2050-084X2016-02-01510.7554/eLife.11273Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxinChanhyung Bae0Claudio Anselmi1https://orcid.org/0000-0002-3017-5085Jeet Kalia2Andres Jara-Oseguera3Charles D Schwieters4Dmitriy Krepkiy5Chul Won Lee6Eun-Hee Kim7Jae Il Kim8José D Faraldo-Gómez9https://orcid.org/0000-0001-7224-7676Kenton J Swartz10https://orcid.org/0000-0003-3419-0765Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States; Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Republic of KoreaTheoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United StatesMolecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States; Indian Institute of Science Education and Research, Pune, Pune, IndiaMolecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United StatesDivision of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, United StatesMolecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United StatesDepartment of Chemistry, Chonnam National University, Gwanju, Republic of KoreaProtein Structure Research Group, Korea Basic Science Institute, Ochang, Republic of KoreaDepartment of Life Science, Gwangju Institute of Science and Technology, Gwangju, Republic of KoreaTheoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United StatesMolecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United StatesVenom toxins are invaluable tools for exploring the structure and mechanisms of ion channels. Here, we solve the structure of double-knot toxin (DkTx), a tarantula toxin that activates the heat-activated TRPV1 channel. We also provide improved structures of TRPV1 with and without the toxin bound, and investigate the interactions of DkTx with the channel and membranes. We find that DkTx binds to the outer edge of the external pore of TRPV1 in a counterclockwise configuration, using a limited protein-protein interface and inserting hydrophobic residues into the bilayer. We also show that DkTx partitions naturally into membranes, with the two lobes exhibiting opposing energetics for membrane partitioning and channel activation. Finally, we find that the toxin disrupts a cluster of hydrophobic residues behind the selectivity filter that are critical for channel activation. Collectively, our findings reveal a novel mode of toxin-channel recognition that has important implications for the mechanism of thermosensation.https://elifesciences.org/articles/11273capsaicinthermosensingmembrane channelmembrane structureprotein-protein interactions in membranes |
| spellingShingle | Chanhyung Bae Claudio Anselmi Jeet Kalia Andres Jara-Oseguera Charles D Schwieters Dmitriy Krepkiy Chul Won Lee Eun-Hee Kim Jae Il Kim José D Faraldo-Gómez Kenton J Swartz Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxin eLife capsaicin thermosensing membrane channel membrane structure protein-protein interactions in membranes |
| title | Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxin |
| title_full | Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxin |
| title_fullStr | Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxin |
| title_full_unstemmed | Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxin |
| title_short | Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxin |
| title_sort | structural insights into the mechanism of activation of the trpv1 channel by a membrane bound tarantula toxin |
| topic | capsaicin thermosensing membrane channel membrane structure protein-protein interactions in membranes |
| url | https://elifesciences.org/articles/11273 |
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