RyR1-related myopathy mutations in ATP and calcium binding sites impair channel regulation

Abstract The type 1 ryanodine receptor (RyR1) is an intracellular calcium (Ca2+) release channel on the sarcoplasmic/endoplasmic reticulum that is required for skeletal muscle contraction. RyR1 channel activity is modulated by ligands, including the activators Ca2+ and ATP. Patients with inherited m...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Qi Yuan, Haikel Dridi, Oliver B. Clarke, Steven Reiken, Zephan Melville, Anetta Wronska, Alexander Kushnir, Ran Zalk, Leah Sittenfeld, Andrew R. Marks
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/19800ceb1bb3470a8e10bc36391ea39b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:19800ceb1bb3470a8e10bc36391ea39b
record_format	dspace
spelling	oai:doaj.org-article:19800ceb1bb3470a8e10bc36391ea39b2021-11-28T12:09:10ZRyR1-related myopathy mutations in ATP and calcium binding sites impair channel regulation10.1186/s40478-021-01287-32051-5960https://doaj.org/article/19800ceb1bb3470a8e10bc36391ea39b2021-11-01T00:00:00Zhttps://doi.org/10.1186/s40478-021-01287-3https://doaj.org/toc/2051-5960Abstract The type 1 ryanodine receptor (RyR1) is an intracellular calcium (Ca2+) release channel on the sarcoplasmic/endoplasmic reticulum that is required for skeletal muscle contraction. RyR1 channel activity is modulated by ligands, including the activators Ca2+ and ATP. Patients with inherited mutations in RyR1 may exhibit muscle weakness as part of a heterogeneous, complex disorder known as RYR1-related myopathy (RYR1-RM) or more recently termed RYR1-related disorders (RYR1-RD). Guided by high-resolution structures of skeletal muscle RyR1, obtained using cryogenic electron microscopy, we introduced mutations into putative Ca2+ and ATP binding sites and studied the function of the resulting mutant channels. These mutations confirmed the functional significance of the Ca2+ and ATP binding sites identified by structural studies based on the effects on channel regulation. Under normal conditions, Ca2+ activates RyR1 at low concentrations (µM) and inhibits it at high concentrations (mM). Mutations in the Ca2+-binding site impaired both activating and inhibitory regulation of the channel, suggesting a single site for both high and low affinity Ca2+-dependent regulation of RyR1 function. Mutation of residues that interact with the adenine ring of ATP abrogated ATP binding to the channel, whereas mutating residues that interact with the triphosphate tail only affected the degree of activation. In addition, patients with mutations at the Ca2+ or ATP binding sites suffer from muscle weakness, therefore impaired RyR1 channel regulation by either Ca2+ or ATP may contribute to the pathophysiology of RYR1-RM in some patients.Qi YuanHaikel DridiOliver B. ClarkeSteven ReikenZephan MelvilleAnetta WronskaAlexander KushnirRan ZalkLeah SittenfeldAndrew R. MarksBMCarticleNeurology. Diseases of the nervous systemRC346-429ENActa Neuropathologica Communications, Vol 9, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurology. Diseases of the nervous system RC346-429
spellingShingle	Neurology. Diseases of the nervous system RC346-429 Qi Yuan Haikel Dridi Oliver B. Clarke Steven Reiken Zephan Melville Anetta Wronska Alexander Kushnir Ran Zalk Leah Sittenfeld Andrew R. Marks RyR1-related myopathy mutations in ATP and calcium binding sites impair channel regulation
description	Abstract The type 1 ryanodine receptor (RyR1) is an intracellular calcium (Ca2+) release channel on the sarcoplasmic/endoplasmic reticulum that is required for skeletal muscle contraction. RyR1 channel activity is modulated by ligands, including the activators Ca2+ and ATP. Patients with inherited mutations in RyR1 may exhibit muscle weakness as part of a heterogeneous, complex disorder known as RYR1-related myopathy (RYR1-RM) or more recently termed RYR1-related disorders (RYR1-RD). Guided by high-resolution structures of skeletal muscle RyR1, obtained using cryogenic electron microscopy, we introduced mutations into putative Ca2+ and ATP binding sites and studied the function of the resulting mutant channels. These mutations confirmed the functional significance of the Ca2+ and ATP binding sites identified by structural studies based on the effects on channel regulation. Under normal conditions, Ca2+ activates RyR1 at low concentrations (µM) and inhibits it at high concentrations (mM). Mutations in the Ca2+-binding site impaired both activating and inhibitory regulation of the channel, suggesting a single site for both high and low affinity Ca2+-dependent regulation of RyR1 function. Mutation of residues that interact with the adenine ring of ATP abrogated ATP binding to the channel, whereas mutating residues that interact with the triphosphate tail only affected the degree of activation. In addition, patients with mutations at the Ca2+ or ATP binding sites suffer from muscle weakness, therefore impaired RyR1 channel regulation by either Ca2+ or ATP may contribute to the pathophysiology of RYR1-RM in some patients.
format	article
author	Qi Yuan Haikel Dridi Oliver B. Clarke Steven Reiken Zephan Melville Anetta Wronska Alexander Kushnir Ran Zalk Leah Sittenfeld Andrew R. Marks
author_facet	Qi Yuan Haikel Dridi Oliver B. Clarke Steven Reiken Zephan Melville Anetta Wronska Alexander Kushnir Ran Zalk Leah Sittenfeld Andrew R. Marks
author_sort	Qi Yuan
title	RyR1-related myopathy mutations in ATP and calcium binding sites impair channel regulation
title_short	RyR1-related myopathy mutations in ATP and calcium binding sites impair channel regulation
title_full	RyR1-related myopathy mutations in ATP and calcium binding sites impair channel regulation
title_fullStr	RyR1-related myopathy mutations in ATP and calcium binding sites impair channel regulation
title_full_unstemmed	RyR1-related myopathy mutations in ATP and calcium binding sites impair channel regulation
title_sort	ryr1-related myopathy mutations in atp and calcium binding sites impair channel regulation
publisher	BMC
publishDate	2021
url	https://doaj.org/article/19800ceb1bb3470a8e10bc36391ea39b
work_keys_str_mv	AT qiyuan ryr1relatedmyopathymutationsinatpandcalciumbindingsitesimpairchannelregulation AT haikeldridi ryr1relatedmyopathymutationsinatpandcalciumbindingsitesimpairchannelregulation AT oliverbclarke ryr1relatedmyopathymutationsinatpandcalciumbindingsitesimpairchannelregulation AT stevenreiken ryr1relatedmyopathymutationsinatpandcalciumbindingsitesimpairchannelregulation AT zephanmelville ryr1relatedmyopathymutationsinatpandcalciumbindingsitesimpairchannelregulation AT anettawronska ryr1relatedmyopathymutationsinatpandcalciumbindingsitesimpairchannelregulation AT alexanderkushnir ryr1relatedmyopathymutationsinatpandcalciumbindingsitesimpairchannelregulation AT ranzalk ryr1relatedmyopathymutationsinatpandcalciumbindingsitesimpairchannelregulation AT leahsittenfeld ryr1relatedmyopathymutationsinatpandcalciumbindingsitesimpairchannelregulation AT andrewrmarks ryr1relatedmyopathymutationsinatpandcalciumbindingsitesimpairchannelregulation
_version_	1718408124322283520

RyR1-related myopathy mutations in ATP and calcium binding sites impair channel regulation

Ejemplares similares