Disease mutations in the ryanodine receptor N-terminal region couple to a mobile intersubunit interface

Ryanodine receptors are large channels that release Ca2+ 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 th...

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Main Authors:	Kimlicka, Lynn, Lau, Kelvin, Tung, Ching-Chieh, Van Petegem, Filip
Format:	Online
Language:	English
Published:	Nature Pub. Group 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586727/

id	pubmed-3586727
recordtype	oai_dc
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 Article Ryanodine receptors are large channels that release Ca2+ 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/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Kimlicka, Lynn Lau, Kelvin Tung, Ching-Chieh Van Petegem, Filip
spellingShingle	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
author_facet	Kimlicka, Lynn Lau, Kelvin Tung, Ching-Chieh Van Petegem, Filip
author_sort	Kimlicka, Lynn
title	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_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_sort	disease mutations in the ryanodine receptor n-terminal region couple to a mobile intersubunit interface
description	Ryanodine receptors are large channels that release Ca2+ 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.
publisher	Nature Pub. Group
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586727/
_version_	1611959031430119424

Disease mutations in the ryanodine receptor N-terminal region couple to a mobile intersubunit interface

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