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Structure of full-length human TRPM4
Transient receptor potential melastatin subfamily member 4 (TRPM4) is a widely distributed, calcium-activated, monovalent-selective cation channel. Mutations in human TRPM4 (hTRPM4) result in progressive familial heart block. Here, we report the electron cryomicroscopy structure of hTRPM4 in a close...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877947/ https://www.ncbi.nlm.nih.gov/pubmed/29463718 http://dx.doi.org/10.1073/pnas.1722038115 |
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author | Duan, Jingjing Li, Zongli Li, Jian Santa-Cruz, Ana Sanchez-Martinez, Silvia Zhang, Jin Clapham, David E. |
author_facet | Duan, Jingjing Li, Zongli Li, Jian Santa-Cruz, Ana Sanchez-Martinez, Silvia Zhang, Jin Clapham, David E. |
author_sort | Duan, Jingjing |
collection | PubMed |
description | Transient receptor potential melastatin subfamily member 4 (TRPM4) is a widely distributed, calcium-activated, monovalent-selective cation channel. Mutations in human TRPM4 (hTRPM4) result in progressive familial heart block. Here, we report the electron cryomicroscopy structure of hTRPM4 in a closed, Na(+)-bound, apo state at pH 7.5 to an overall resolution of 3.7 Å. Five partially hydrated sodium ions are proposed to occupy the center of the conduction pore and the entrance to the coiled-coil domain. We identify an upper gate in the selectivity filter and a lower gate at the entrance to the cytoplasmic coiled-coil domain. Intramolecular interactions exist between the TRP domain and the S4–S5 linker, N-terminal domain, and N and C termini. Finally, we identify aromatic interactions via π–π bonds and cation–π bonds, glycosylation at an N-linked extracellular site, a pore-loop disulfide bond, and 24 lipid binding sites. We compare and contrast this structure with other TRP channels and discuss potential mechanisms of regulation and gating of human full-length TRPM4. |
format | Online Article Text |
id | pubmed-5877947 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-58779472018-04-02 Structure of full-length human TRPM4 Duan, Jingjing Li, Zongli Li, Jian Santa-Cruz, Ana Sanchez-Martinez, Silvia Zhang, Jin Clapham, David E. Proc Natl Acad Sci U S A Biological Sciences Transient receptor potential melastatin subfamily member 4 (TRPM4) is a widely distributed, calcium-activated, monovalent-selective cation channel. Mutations in human TRPM4 (hTRPM4) result in progressive familial heart block. Here, we report the electron cryomicroscopy structure of hTRPM4 in a closed, Na(+)-bound, apo state at pH 7.5 to an overall resolution of 3.7 Å. Five partially hydrated sodium ions are proposed to occupy the center of the conduction pore and the entrance to the coiled-coil domain. We identify an upper gate in the selectivity filter and a lower gate at the entrance to the cytoplasmic coiled-coil domain. Intramolecular interactions exist between the TRP domain and the S4–S5 linker, N-terminal domain, and N and C termini. Finally, we identify aromatic interactions via π–π bonds and cation–π bonds, glycosylation at an N-linked extracellular site, a pore-loop disulfide bond, and 24 lipid binding sites. We compare and contrast this structure with other TRP channels and discuss potential mechanisms of regulation and gating of human full-length TRPM4. National Academy of Sciences 2018-03-06 2018-02-20 /pmc/articles/PMC5877947/ /pubmed/29463718 http://dx.doi.org/10.1073/pnas.1722038115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Duan, Jingjing Li, Zongli Li, Jian Santa-Cruz, Ana Sanchez-Martinez, Silvia Zhang, Jin Clapham, David E. Structure of full-length human TRPM4 |
title | Structure of full-length human TRPM4 |
title_full | Structure of full-length human TRPM4 |
title_fullStr | Structure of full-length human TRPM4 |
title_full_unstemmed | Structure of full-length human TRPM4 |
title_short | Structure of full-length human TRPM4 |
title_sort | structure of full-length human trpm4 |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877947/ https://www.ncbi.nlm.nih.gov/pubmed/29463718 http://dx.doi.org/10.1073/pnas.1722038115 |
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