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Disease mutations in the ryanodine receptor N-terminal region couple to a mobile intersubunit interface
Ryanodine receptors are large channels that release Ca(2+) from the endoplasmic and sarcoplasmic reticulum. Hundreds of RyR mutations can cause cardiac and skeletal muscle disorders, yet detailed mechanisms explaining their effects have been lacking. Here we compare pseudo-atomic models and propose...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Pub. Group
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586727/ https://www.ncbi.nlm.nih.gov/pubmed/23422674 http://dx.doi.org/10.1038/ncomms2501 |
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author | Kimlicka, Lynn Lau, Kelvin Tung, Ching-Chieh Van Petegem, Filip |
author_facet | Kimlicka, Lynn Lau, Kelvin Tung, Ching-Chieh Van Petegem, Filip |
author_sort | Kimlicka, Lynn |
collection | PubMed |
description | Ryanodine receptors are large channels that release Ca(2+) from the endoplasmic and sarcoplasmic reticulum. Hundreds of RyR mutations can cause cardiac and skeletal muscle disorders, yet detailed mechanisms explaining their effects have been lacking. Here we compare pseudo-atomic models and propose that channel opening coincides with widening of a cytoplasmic vestibule formed by the N-terminal region, thus altering an interface targeted by 20 disease mutations. We solve crystal structures of several disease mutants that affect intrasubunit domain–domain interfaces. Mutations affecting intrasubunit ionic pairs alter relative domain orientations, and thus couple to surrounding interfaces. Buried disease mutations cause structural changes that also connect to the intersubunit contact area. These results suggest that the intersubunit contact region between N-terminal domains is a prime target for disease mutations, direct or indirect, and we present a model whereby ryanodine receptors and inositol-1,4,5-trisphosphate receptors are activated by altering domain arrangements in the N-terminal region. |
format | Online Article Text |
id | pubmed-3586727 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Nature Pub. Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-35867272013-03-05 Disease mutations in the ryanodine receptor N-terminal region couple to a mobile intersubunit interface Kimlicka, Lynn Lau, Kelvin Tung, Ching-Chieh Van Petegem, Filip Nat Commun Article Ryanodine receptors are large channels that release Ca(2+) from the endoplasmic and sarcoplasmic reticulum. Hundreds of RyR mutations can cause cardiac and skeletal muscle disorders, yet detailed mechanisms explaining their effects have been lacking. Here we compare pseudo-atomic models and propose that channel opening coincides with widening of a cytoplasmic vestibule formed by the N-terminal region, thus altering an interface targeted by 20 disease mutations. We solve crystal structures of several disease mutants that affect intrasubunit domain–domain interfaces. Mutations affecting intrasubunit ionic pairs alter relative domain orientations, and thus couple to surrounding interfaces. Buried disease mutations cause structural changes that also connect to the intersubunit contact area. These results suggest that the intersubunit contact region between N-terminal domains is a prime target for disease mutations, direct or indirect, and we present a model whereby ryanodine receptors and inositol-1,4,5-trisphosphate receptors are activated by altering domain arrangements in the N-terminal region. Nature Pub. Group 2013-02-19 /pmc/articles/PMC3586727/ /pubmed/23422674 http://dx.doi.org/10.1038/ncomms2501 Text en Copyright © 2013, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/ |
spellingShingle | Article Kimlicka, Lynn Lau, Kelvin Tung, Ching-Chieh Van Petegem, Filip Disease mutations in the ryanodine receptor N-terminal region couple to a mobile intersubunit interface |
title | Disease mutations in the ryanodine receptor N-terminal region couple to a mobile intersubunit interface |
title_full | Disease mutations in the ryanodine receptor N-terminal region couple to a mobile intersubunit interface |
title_fullStr | Disease mutations in the ryanodine receptor N-terminal region couple to a mobile intersubunit interface |
title_full_unstemmed | Disease mutations in the ryanodine receptor N-terminal region couple to a mobile intersubunit interface |
title_short | Disease mutations in the ryanodine receptor N-terminal region couple to a mobile intersubunit interface |
title_sort | disease mutations in the ryanodine receptor n-terminal region couple to a mobile intersubunit interface |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586727/ https://www.ncbi.nlm.nih.gov/pubmed/23422674 http://dx.doi.org/10.1038/ncomms2501 |
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