Global alignment and assessment of TRP channel transmembrane domain structures to explore functional mechanisms
The recent proliferation of published TRP channel structures provides a foundation for understanding the diverse functional properties of this important family of ion channel proteins. To facilitate mechanistic investigations, we constructed a structure-based alignment of the transmembrane domains o...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/58660 |
| _version_ | 1818028519014268928 |
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| author | Katherine E Huffer Antoniya A Aleksandrova Andrés Jara-Oseguera Lucy R Forrest Kenton J Swartz |
| author_facet | Katherine E Huffer Antoniya A Aleksandrova Andrés Jara-Oseguera Lucy R Forrest Kenton J Swartz |
| author_sort | Katherine E Huffer |
| collection | DOAJ |
| description | The recent proliferation of published TRP channel structures provides a foundation for understanding the diverse functional properties of this important family of ion channel proteins. To facilitate mechanistic investigations, we constructed a structure-based alignment of the transmembrane domains of 120 TRP channel structures. Comparison of structures determined in the absence or presence of activating stimuli reveals similar constrictions in the central ion permeation pathway near the intracellular end of the S6 helices, pointing to a conserved cytoplasmic gate and suggesting that most available structures represent non-conducting states. Comparison of the ion selectivity filters toward the extracellular end of the pore supports existing hypotheses for mechanisms of ion selectivity. Also conserved to varying extents are hot spots for interactions with hydrophobic ligands, lipids and ions, as well as discrete alterations in helix conformations. This analysis therefore provides a framework for investigating the structural basis of TRP channel gating mechanisms and pharmacology, and, despite the large number of structures included, reveals the need for additional structural data and for more functional studies to establish the mechanistic basis of TRP channel function. |
| first_indexed | 2024-12-10T05:05:05Z |
| format | Article |
| id | doaj.art-76a3f39f1b384dc092a8fd5a535a5edd |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T05:05:05Z |
| publishDate | 2020-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-76a3f39f1b384dc092a8fd5a535a5edd2022-12-22T02:01:17ZengeLife Sciences Publications LtdeLife2050-084X2020-08-01910.7554/eLife.58660Global alignment and assessment of TRP channel transmembrane domain structures to explore functional mechanismsKatherine E Huffer0https://orcid.org/0000-0001-5003-3140Antoniya A Aleksandrova1https://orcid.org/0000-0001-7393-1787Andrés Jara-Oseguera2https://orcid.org/0000-0001-5921-9320Lucy R Forrest3https://orcid.org/0000-0003-1855-7985Kenton J Swartz4https://orcid.org/0000-0003-3419-0765Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, United StatesComputational Structural Biology Section, Porter Neuroscience Research Center, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, United StatesMolecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, United StatesComputational Structural Biology Section, Porter Neuroscience Research Center, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, United StatesMolecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, United StatesThe recent proliferation of published TRP channel structures provides a foundation for understanding the diverse functional properties of this important family of ion channel proteins. To facilitate mechanistic investigations, we constructed a structure-based alignment of the transmembrane domains of 120 TRP channel structures. Comparison of structures determined in the absence or presence of activating stimuli reveals similar constrictions in the central ion permeation pathway near the intracellular end of the S6 helices, pointing to a conserved cytoplasmic gate and suggesting that most available structures represent non-conducting states. Comparison of the ion selectivity filters toward the extracellular end of the pore supports existing hypotheses for mechanisms of ion selectivity. Also conserved to varying extents are hot spots for interactions with hydrophobic ligands, lipids and ions, as well as discrete alterations in helix conformations. This analysis therefore provides a framework for investigating the structural basis of TRP channel gating mechanisms and pharmacology, and, despite the large number of structures included, reveals the need for additional structural data and for more functional studies to establish the mechanistic basis of TRP channel function.https://elifesciences.org/articles/58660TRP channelion channel gatestructural alignmentmembrane protein structure |
| spellingShingle | Katherine E Huffer Antoniya A Aleksandrova Andrés Jara-Oseguera Lucy R Forrest Kenton J Swartz Global alignment and assessment of TRP channel transmembrane domain structures to explore functional mechanisms eLife TRP channel ion channel gate structural alignment membrane protein structure |
| title | Global alignment and assessment of TRP channel transmembrane domain structures to explore functional mechanisms |
| title_full | Global alignment and assessment of TRP channel transmembrane domain structures to explore functional mechanisms |
| title_fullStr | Global alignment and assessment of TRP channel transmembrane domain structures to explore functional mechanisms |
| title_full_unstemmed | Global alignment and assessment of TRP channel transmembrane domain structures to explore functional mechanisms |
| title_short | Global alignment and assessment of TRP channel transmembrane domain structures to explore functional mechanisms |
| title_sort | global alignment and assessment of trp channel transmembrane domain structures to explore functional mechanisms |
| topic | TRP channel ion channel gate structural alignment membrane protein structure |
| url | https://elifesciences.org/articles/58660 |
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