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Structure, Dynamics and Implied Gating Mechanism of a Human Cyclic Nucleotide-Gated Channel
Cyclic nucleotide-gated (CNG) ion channels are nonselective cation channels, essential for visual and olfactory sensory transduction. Although the channels include voltage-sensor domains (VSDs), their conductance is thought to be independent of the membrane potential, and their gating regulated by c...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256070/ https://www.ncbi.nlm.nih.gov/pubmed/25474149 http://dx.doi.org/10.1371/journal.pcbi.1003976 |
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author | Gofman, Yana Schärfe, Charlotta Marks, Debora S. Haliloglu, Turkan Ben-Tal, Nir |
author_facet | Gofman, Yana Schärfe, Charlotta Marks, Debora S. Haliloglu, Turkan Ben-Tal, Nir |
author_sort | Gofman, Yana |
collection | PubMed |
description | Cyclic nucleotide-gated (CNG) ion channels are nonselective cation channels, essential for visual and olfactory sensory transduction. Although the channels include voltage-sensor domains (VSDs), their conductance is thought to be independent of the membrane potential, and their gating regulated by cytosolic cyclic nucleotide–binding domains. Mutations in these channels result in severe, degenerative retinal diseases, which remain untreatable. The lack of structural information on CNG channels has prevented mechanistic understanding of disease-causing mutations, precluded structure-based drug design, and hampered in silico investigation of the gating mechanism. To address this, we built a 3D model of the cone tetrameric CNG channel, based on homology to two distinct templates with known structures: the transmembrane (TM) domain of a bacterial channel, and the cyclic nucleotide-binding domain of the mouse HCN2 channel. Since the TM-domain template had low sequence-similarity to the TM domains of the CNG channels, and to reconcile conflicts between the two templates, we developed a novel, hybrid approach, combining homology modeling with evolutionary coupling constraints. Next, we used elastic network analysis of the model structure to investigate global motions of the channel and to elucidate its gating mechanism. We found the following: (i) In the main mode of motion, the TM and cytosolic domains counter-rotated around the membrane normal. We related this motion to gating, a proposition that is supported by previous experimental data, and by comparison to the known gating mechanism of the bacterial KirBac channel. (ii) The VSDs could facilitate gating (supplementing the pore gate), explaining their presence in such ‘voltage-insensitive’ channels. (iii) Our elastic network model analysis of the CNGA3 channel supports a modular model of allosteric gating, according to which protein domains are quasi-independent: they can move independently, but are coupled to each other allosterically. |
format | Online Article Text |
id | pubmed-4256070 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-42560702014-12-11 Structure, Dynamics and Implied Gating Mechanism of a Human Cyclic Nucleotide-Gated Channel Gofman, Yana Schärfe, Charlotta Marks, Debora S. Haliloglu, Turkan Ben-Tal, Nir PLoS Comput Biol Research Article Cyclic nucleotide-gated (CNG) ion channels are nonselective cation channels, essential for visual and olfactory sensory transduction. Although the channels include voltage-sensor domains (VSDs), their conductance is thought to be independent of the membrane potential, and their gating regulated by cytosolic cyclic nucleotide–binding domains. Mutations in these channels result in severe, degenerative retinal diseases, which remain untreatable. The lack of structural information on CNG channels has prevented mechanistic understanding of disease-causing mutations, precluded structure-based drug design, and hampered in silico investigation of the gating mechanism. To address this, we built a 3D model of the cone tetrameric CNG channel, based on homology to two distinct templates with known structures: the transmembrane (TM) domain of a bacterial channel, and the cyclic nucleotide-binding domain of the mouse HCN2 channel. Since the TM-domain template had low sequence-similarity to the TM domains of the CNG channels, and to reconcile conflicts between the two templates, we developed a novel, hybrid approach, combining homology modeling with evolutionary coupling constraints. Next, we used elastic network analysis of the model structure to investigate global motions of the channel and to elucidate its gating mechanism. We found the following: (i) In the main mode of motion, the TM and cytosolic domains counter-rotated around the membrane normal. We related this motion to gating, a proposition that is supported by previous experimental data, and by comparison to the known gating mechanism of the bacterial KirBac channel. (ii) The VSDs could facilitate gating (supplementing the pore gate), explaining their presence in such ‘voltage-insensitive’ channels. (iii) Our elastic network model analysis of the CNGA3 channel supports a modular model of allosteric gating, according to which protein domains are quasi-independent: they can move independently, but are coupled to each other allosterically. Public Library of Science 2014-12-04 /pmc/articles/PMC4256070/ /pubmed/25474149 http://dx.doi.org/10.1371/journal.pcbi.1003976 Text en © 2014 Gofman et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Gofman, Yana Schärfe, Charlotta Marks, Debora S. Haliloglu, Turkan Ben-Tal, Nir Structure, Dynamics and Implied Gating Mechanism of a Human Cyclic Nucleotide-Gated Channel |
title | Structure, Dynamics and Implied Gating Mechanism of a Human Cyclic Nucleotide-Gated Channel |
title_full | Structure, Dynamics and Implied Gating Mechanism of a Human Cyclic Nucleotide-Gated Channel |
title_fullStr | Structure, Dynamics and Implied Gating Mechanism of a Human Cyclic Nucleotide-Gated Channel |
title_full_unstemmed | Structure, Dynamics and Implied Gating Mechanism of a Human Cyclic Nucleotide-Gated Channel |
title_short | Structure, Dynamics and Implied Gating Mechanism of a Human Cyclic Nucleotide-Gated Channel |
title_sort | structure, dynamics and implied gating mechanism of a human cyclic nucleotide-gated channel |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256070/ https://www.ncbi.nlm.nih.gov/pubmed/25474149 http://dx.doi.org/10.1371/journal.pcbi.1003976 |
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