Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3

hnRNPDL is a ribonucleoprotein (RNP) involved in transcription and RNA-processing that hosts missense mutations causing limb-girdle muscular dystrophy D3 (LGMD D3). Mammalian-specific alternative splicing (AS) renders three natural isoforms, hnRNPDL-2 being predominant in humans. We present the cryo...

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Autores: Garcia-Pardo, Javier|||0000-0001-9179-6371, Bartolomé-Nafría, Andrea|||0000-0003-3114-1415, Chaves-Sanjuan, Antonio|||0000-0003-3287-9024, Gil-Garcia, Marcos|||0000-0002-7457-7860, Visentin, Cristina|||0000-0003-2705-1417, Bolognesi, Martino|||0000-0002-9253-5170, Ricagno, Stefano|||0000-0001-6678-5873, Ventura, Salvador|||0000-0002-9652-6351
Formato: artículo
Fecha de publicación:2023
País:España
Recursos:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:270882
Acesso em linha:https://ddd.uab.cat/record/270882
https://dx.doi.org/urn:doi:10.1038/s41467-023-35854-0
Access Level:acceso abierto
Palavra-chave:Cryoelectron microscopy
Alternative splicing
Protein aggregation
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spelling Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3Garcia-Pardo, Javier|||0000-0001-9179-6371Bartolomé-Nafría, Andrea|||0000-0003-3114-1415Chaves-Sanjuan, Antonio|||0000-0003-3287-9024Gil-Garcia, Marcos|||0000-0002-7457-7860Visentin, Cristina|||0000-0003-2705-1417Bolognesi, Martino|||0000-0002-9253-5170Ricagno, Stefano|||0000-0001-6678-5873Ventura, Salvador|||0000-0002-9652-6351Cryoelectron microscopyAlternative splicingProtein aggregationhnRNPDL is a ribonucleoprotein (RNP) involved in transcription and RNA-processing that hosts missense mutations causing limb-girdle muscular dystrophy D3 (LGMD D3). Mammalian-specific alternative splicing (AS) renders three natural isoforms, hnRNPDL-2 being predominant in humans. We present the cryo-electron microscopy structure of full-length hnRNPDL-2 amyloid fibrils, which are stable, non-toxic, and bind nucleic acids. The high-resolution amyloid core consists of a single Gly/Tyr-rich and highly hydrophilic filament containing internal water channels. The RNA binding domains are located as a solenoidal coat around the core. The architecture and activity of hnRNPDL-2 fibrils are reminiscent of functional amyloids, our results suggesting that LGMD D3 might be a loss-of-function disease associated with impaired fibrillation. Strikingly, the fibril core matches exon 6, absent in the soluble hnRNPDL-3 isoform. This provides structural evidence for AS controlling hnRNPDL assembly by precisely including/skipping an amyloid exon, a mechanism that holds the potential to generate functional diversity in RNPs. The authors report the Cryo-EM of hnRNPDL-2 fibrils. The structure highlights features of a functional amyloid associated with limb-girdle muscular dystrophy-3 and explains how alternative splicing controls the assembly of this ribonucleoprotein. 22023-01-0120232023-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/270882https://dx.doi.org/urn:doi:10.1038/s41467-023-35854-0reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengEuropean Commission https://doi.org/10.13039/501100000780 952334Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2019-105017RB-I00Ministerio de Ciencia e Innovación https://doi.org/10.13039/501100004837 IJC2019-041039-IMinisterio de Educación, Cultura y Deporte https://doi.org/10.13039/501100003176 FPU16/02465open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2708822026-06-06T12:50:31Z
dc.title.none.fl_str_mv Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3
title Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3
spellingShingle Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3
Garcia-Pardo, Javier|||0000-0001-9179-6371
Cryoelectron microscopy
Alternative splicing
Protein aggregation
title_short Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3
title_full Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3
title_fullStr Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3
title_full_unstemmed Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3
title_sort Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3
dc.creator.none.fl_str_mv Garcia-Pardo, Javier|||0000-0001-9179-6371
Bartolomé-Nafría, Andrea|||0000-0003-3114-1415
Chaves-Sanjuan, Antonio|||0000-0003-3287-9024
Gil-Garcia, Marcos|||0000-0002-7457-7860
Visentin, Cristina|||0000-0003-2705-1417
Bolognesi, Martino|||0000-0002-9253-5170
Ricagno, Stefano|||0000-0001-6678-5873
Ventura, Salvador|||0000-0002-9652-6351
author Garcia-Pardo, Javier|||0000-0001-9179-6371
author_facet Garcia-Pardo, Javier|||0000-0001-9179-6371
Bartolomé-Nafría, Andrea|||0000-0003-3114-1415
Chaves-Sanjuan, Antonio|||0000-0003-3287-9024
Gil-Garcia, Marcos|||0000-0002-7457-7860
Visentin, Cristina|||0000-0003-2705-1417
Bolognesi, Martino|||0000-0002-9253-5170
Ricagno, Stefano|||0000-0001-6678-5873
Ventura, Salvador|||0000-0002-9652-6351
author_role author
author2 Bartolomé-Nafría, Andrea|||0000-0003-3114-1415
Chaves-Sanjuan, Antonio|||0000-0003-3287-9024
Gil-Garcia, Marcos|||0000-0002-7457-7860
Visentin, Cristina|||0000-0003-2705-1417
Bolognesi, Martino|||0000-0002-9253-5170
Ricagno, Stefano|||0000-0001-6678-5873
Ventura, Salvador|||0000-0002-9652-6351
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cryoelectron microscopy
Alternative splicing
Protein aggregation
topic Cryoelectron microscopy
Alternative splicing
Protein aggregation
description hnRNPDL is a ribonucleoprotein (RNP) involved in transcription and RNA-processing that hosts missense mutations causing limb-girdle muscular dystrophy D3 (LGMD D3). Mammalian-specific alternative splicing (AS) renders three natural isoforms, hnRNPDL-2 being predominant in humans. We present the cryo-electron microscopy structure of full-length hnRNPDL-2 amyloid fibrils, which are stable, non-toxic, and bind nucleic acids. The high-resolution amyloid core consists of a single Gly/Tyr-rich and highly hydrophilic filament containing internal water channels. The RNA binding domains are located as a solenoidal coat around the core. The architecture and activity of hnRNPDL-2 fibrils are reminiscent of functional amyloids, our results suggesting that LGMD D3 might be a loss-of-function disease associated with impaired fibrillation. Strikingly, the fibril core matches exon 6, absent in the soluble hnRNPDL-3 isoform. This provides structural evidence for AS controlling hnRNPDL assembly by precisely including/skipping an amyloid exon, a mechanism that holds the potential to generate functional diversity in RNPs. The authors report the Cryo-EM of hnRNPDL-2 fibrils. The structure highlights features of a functional amyloid associated with limb-girdle muscular dystrophy-3 and explains how alternative splicing controls the assembly of this ribonucleoprotein.
publishDate 2023
dc.date.none.fl_str_mv 2
2023-01-01
2023
2023-01-01
dc.type.none.fl_str_mv 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://ddd.uab.cat/record/270882
https://dx.doi.org/urn:doi:10.1038/s41467-023-35854-0
url https://ddd.uab.cat/record/270882
https://dx.doi.org/urn:doi:10.1038/s41467-023-35854-0
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv European Commission https://doi.org/10.13039/501100000780 952334
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2019-105017RB-I00
Ministerio de Ciencia e Innovación https://doi.org/10.13039/501100004837 IJC2019-041039-I
Ministerio de Educación, Cultura y Deporte https://doi.org/10.13039/501100003176 FPU16/02465
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/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
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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