New insights into the molecular mechanism of rhodopsin retinitis pigmentosa from the biochemical and functional characterization of G90V, Y102H and I307N mutations

Mutations in the photoreceptor protein rhodopsin are known as one of the leading causes of retinal degeneration in humans. Two rhodopsin mutations, Y102H and I307N, obtained in chemically mutagenized mice, are currently the subject of increased interest as relevant models for studying the process of...

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Autores: Herrera Hernández, María Guadalupe, Razzaghi, Neda, Fernández González, Pol|||0000-0001-6136-763X, Bosch Presegue, Laia, Vila i Julià, Guillem|||0000-0001-5576-7442, Pérez González, Juan Jesús|||0000-0002-0748-8147, Garriga Solé, Pere|||0000-0003-4234-8382
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universitat Politècnica de Catalunya (UPC)
Repositorio:UPCommons. Portal del coneixement obert de la UPC
Idioma:inglés
OAI Identifier:oai:upcommons.upc.edu:2117/383863
Acceso en línea:https://hdl.handle.net/2117/383863
https://dx.doi.org/10.1007/s00018-021-04086-0
Access Level:acceso abierto
Palabra clave:Retinal degeneration
Protein folding
Ligand binding (Biochemistry)
Retinal degenerative diseases
G protein-coupled receptors
Conformational stability
Ligand binding
Lligands (Bioquímica)
Degeneració macular
Retina -- Malalties
Àrees temàtiques de la UPC::Ciències de la visió
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spelling New insights into the molecular mechanism of rhodopsin retinitis pigmentosa from the biochemical and functional characterization of G90V, Y102H and I307N mutationsHerrera Hernández, María GuadalupeRazzaghi, NedaFernández González, Pol|||0000-0001-6136-763XBosch Presegue, LaiaVila i Julià, Guillem|||0000-0001-5576-7442Pérez González, Juan Jesús|||0000-0002-0748-8147Garriga Solé, Pere|||0000-0003-4234-8382Retinal degenerationProtein foldingLigand binding (Biochemistry)Retinal degenerative diseasesG protein-coupled receptorsProtein foldingConformational stabilityLigand bindingLligands (Bioquímica)Degeneració macularRetina -- MalaltiesÀrees temàtiques de la UPC::Ciències de la visióMutations in the photoreceptor protein rhodopsin are known as one of the leading causes of retinal degeneration in humans. Two rhodopsin mutations, Y102H and I307N, obtained in chemically mutagenized mice, are currently the subject of increased interest as relevant models for studying the process of retinal degeneration in humans. Here, we report on the biochemical and functional characterization of the structural and functional alterations of these two rhodopsin mutants and we compare them with the G90V mutant previously analyzed, as a basis for a better understanding of in vivo studies. This mechanis- tic knowledge is fundamental to use it for developing novel therapeutic approaches for the treatment of inherited retinal degeneration in retinitis pigmentosa. We find that Y102H and I307N mutations affect the inactive–active equilibrium of the receptor. In this regard, the mutations reduce the stability of the inactive conformation but increase the stability of the active conformation. Furthermore, the initial rate of the functional activation of transducin, by the I307N mutant is reduced, but its kinetic profile shows an unusual increase with time suggesting a profound effect on the signal transduction process. This latter effect can be associated with a change in the flexibility of helix 7 and an indirect effect of the mutation on helix 8 and the C-terminal tail of rhodopsin, whose potential role in the functional activation of the receptor has been usually underes- timated. In the case of the Y102H mutant, the observed changes can be associated with conformational alterations affecting the folding of the rhodopsin intradiscal domain, and its presumed involvement in the retinal binding process by the receptor.This research was supported by Grant PID2019-104817GB-I00 from Ministerio de Ciencia e Innovación (MICINN)Peer ReviewedSpringer Nature20222022-01-0120232023-02-22journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/pdfhttps://hdl.handle.net/2117/383863https://dx.doi.org/10.1007/s00018-021-04086-0reponame:UPCommons. Portal del coneixement obert de la UPCinstname:Universitat Politècnica de Catalunya (UPC)InglésengAgencia Estatal de Investigación http://doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 PID2019-104817GB-I00 NUEVOS LIGANDOS ALOSTERICOS DEL RECEPTOR ACOPLADO A PROTEINA G VISUAL RODOPSINA Y EL MECANISMO MOLECULAR DE ENFERMEDADES DEGENERATIVAS DE LA RETINAopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:upcommons.upc.edu:2117/3838632026-05-27T15:37:01Z
dc.title.none.fl_str_mv New insights into the molecular mechanism of rhodopsin retinitis pigmentosa from the biochemical and functional characterization of G90V, Y102H and I307N mutations
title New insights into the molecular mechanism of rhodopsin retinitis pigmentosa from the biochemical and functional characterization of G90V, Y102H and I307N mutations
spellingShingle New insights into the molecular mechanism of rhodopsin retinitis pigmentosa from the biochemical and functional characterization of G90V, Y102H and I307N mutations
Herrera Hernández, María Guadalupe
Retinal degeneration
Protein folding
Ligand binding (Biochemistry)
Retinal degenerative diseases
G protein-coupled receptors
Protein folding
Conformational stability
Ligand binding
Lligands (Bioquímica)
Degeneració macular
Retina -- Malalties
Àrees temàtiques de la UPC::Ciències de la visió
title_short New insights into the molecular mechanism of rhodopsin retinitis pigmentosa from the biochemical and functional characterization of G90V, Y102H and I307N mutations
title_full New insights into the molecular mechanism of rhodopsin retinitis pigmentosa from the biochemical and functional characterization of G90V, Y102H and I307N mutations
title_fullStr New insights into the molecular mechanism of rhodopsin retinitis pigmentosa from the biochemical and functional characterization of G90V, Y102H and I307N mutations
title_full_unstemmed New insights into the molecular mechanism of rhodopsin retinitis pigmentosa from the biochemical and functional characterization of G90V, Y102H and I307N mutations
title_sort New insights into the molecular mechanism of rhodopsin retinitis pigmentosa from the biochemical and functional characterization of G90V, Y102H and I307N mutations
dc.creator.none.fl_str_mv Herrera Hernández, María Guadalupe
Razzaghi, Neda
Fernández González, Pol|||0000-0001-6136-763X
Bosch Presegue, Laia
Vila i Julià, Guillem|||0000-0001-5576-7442
Pérez González, Juan Jesús|||0000-0002-0748-8147
Garriga Solé, Pere|||0000-0003-4234-8382
author Herrera Hernández, María Guadalupe
author_facet Herrera Hernández, María Guadalupe
Razzaghi, Neda
Fernández González, Pol|||0000-0001-6136-763X
Bosch Presegue, Laia
Vila i Julià, Guillem|||0000-0001-5576-7442
Pérez González, Juan Jesús|||0000-0002-0748-8147
Garriga Solé, Pere|||0000-0003-4234-8382
author_role author
author2 Razzaghi, Neda
Fernández González, Pol|||0000-0001-6136-763X
Bosch Presegue, Laia
Vila i Julià, Guillem|||0000-0001-5576-7442
Pérez González, Juan Jesús|||0000-0002-0748-8147
Garriga Solé, Pere|||0000-0003-4234-8382
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Retinal degeneration
Protein folding
Ligand binding (Biochemistry)
Retinal degenerative diseases
G protein-coupled receptors
Protein folding
Conformational stability
Ligand binding
Lligands (Bioquímica)
Degeneració macular
Retina -- Malalties
Àrees temàtiques de la UPC::Ciències de la visió
topic Retinal degeneration
Protein folding
Ligand binding (Biochemistry)
Retinal degenerative diseases
G protein-coupled receptors
Protein folding
Conformational stability
Ligand binding
Lligands (Bioquímica)
Degeneració macular
Retina -- Malalties
Àrees temàtiques de la UPC::Ciències de la visió
description Mutations in the photoreceptor protein rhodopsin are known as one of the leading causes of retinal degeneration in humans. Two rhodopsin mutations, Y102H and I307N, obtained in chemically mutagenized mice, are currently the subject of increased interest as relevant models for studying the process of retinal degeneration in humans. Here, we report on the biochemical and functional characterization of the structural and functional alterations of these two rhodopsin mutants and we compare them with the G90V mutant previously analyzed, as a basis for a better understanding of in vivo studies. This mechanis- tic knowledge is fundamental to use it for developing novel therapeutic approaches for the treatment of inherited retinal degeneration in retinitis pigmentosa. We find that Y102H and I307N mutations affect the inactive–active equilibrium of the receptor. In this regard, the mutations reduce the stability of the inactive conformation but increase the stability of the active conformation. Furthermore, the initial rate of the functional activation of transducin, by the I307N mutant is reduced, but its kinetic profile shows an unusual increase with time suggesting a profound effect on the signal transduction process. This latter effect can be associated with a change in the flexibility of helix 7 and an indirect effect of the mutation on helix 8 and the C-terminal tail of rhodopsin, whose potential role in the functional activation of the receptor has been usually underes- timated. In the case of the Y102H mutant, the observed changes can be associated with conformational alterations affecting the folding of the rhodopsin intradiscal domain, and its presumed involvement in the retinal binding process by the receptor.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-01-01
2023
2023-02-22
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/2117/383863
https://dx.doi.org/10.1007/s00018-021-04086-0
url https://hdl.handle.net/2117/383863
https://dx.doi.org/10.1007/s00018-021-04086-0
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación http://doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 PID2019-104817GB-I00 NUEVOS LIGANDOS ALOSTERICOS DEL RECEPTOR ACOPLADO A PROTEINA G VISUAL RODOPSINA Y EL MECANISMO MOLECULAR DE ENFERMEDADES DEGENERATIVAS DE LA RETINA
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:UPCommons. Portal del coneixement obert de la UPC
instname:Universitat Politècnica de Catalunya (UPC)
instname_str Universitat Politècnica de Catalunya (UPC)
reponame_str UPCommons. Portal del coneixement obert de la UPC
collection UPCommons. Portal del coneixement obert de la UPC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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