Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor

Polyglutamine (polyQ) tracts are regions of low sequence complexity frequently found in transcription factors. Tract length often correlates with transcriptional activity and expansion beyond specific thresholds in certain human proteins is the cause of polyQ disorders. To study the structural basis...

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Detalles Bibliográficos
Autores: Escobedo, Albert, Topal, Busra, Kunze, Micha B.A., Aranda, Juan, Chiesa, Giulio, Mungianu, Daniele, Bernardo-Seisdedos, Ganeko, Eftekharzadeh, Bahareh, Gairi, Margarida, Pierattelli, Roberta, Felli, Isabella Caterina, Diercks, Tammo, Millet, Oscar, García, Jesús, Orozco, Modesto, Crehuet, Ramón, Lindorff-Larsen, Kresten, Salvatella, Xavier
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/200649
Acceso en línea:http://hdl.handle.net/10261/200649
Access Level:acceso abierto
Palabra clave:Peptides
Mice
Huntington disease
HD Mouse
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spelling Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factorEscobedo, AlbertTopal, BusraKunze, Micha B.A.Aranda, JuanChiesa, GiulioMungianu, DanieleBernardo-Seisdedos, GanekoEftekharzadeh, BaharehGairi, MargaridaPierattelli, RobertaFelli, Isabella CaterinaDiercks, TammoMillet, OscarGarcía, JesúsOrozco, ModestoCrehuet, RamónLindorff-Larsen, KrestenSalvatella, XavierPeptidesMiceHuntington diseaseHD MousePolyglutamine (polyQ) tracts are regions of low sequence complexity frequently found in transcription factors. Tract length often correlates with transcriptional activity and expansion beyond specific thresholds in certain human proteins is the cause of polyQ disorders. To study the structural basis of the association between tract length, transcriptional activity and disease, we addressed how the conformation of the polyQ tract of the androgen receptor, associated with spinobulbar muscular atrophy (SBMA), depends on its length. Here we report that this sequence folds into a helical structure stabilized by unconventional hydrogen bonds between glutamine side chains and main chain carbonyl groups, and that its helicity directly correlates with tract length. These unusual hydrogen bonds are bifurcate with the conventional hydrogen bonds stabilizing α-helices. Our findings suggest a plausible rationale for the association between polyQ tract length and androgen receptor transcriptional activity and have implications for establishing the mechanistic basis of SBMA. © 2019, The Author(s).We thank Sandro Bottaro, Ernest Giralt, Gerhard Hummer, Víctor Muñoz, and Huan-Xiang Zhou for helpful discussions and the ICTS NMR facility, managed by the scientific and technological centers of the University of Barcelona (CCiT UB), for their help in NMR. K.L.-L. and M.B.A.K. acknowledge funding from the Lundbeck Foundation and the BRAINSTRUC initiative. B.T. and J.A. acknowledge, respectively, FPI and Juan de la Cierva fellowships from MINECO. R.P and I.C.F. acknowledge funding from the European Commission (iNEXT, 653706). M.O. acknowledges the Spanish Ministry of Science (BFU2014-61670-EXP), the Catalan SGR, the Instituto Nacional de Bioinformática, the Biomolecular and Bioinformatics Resources Platform (ISCIII PT 13/0001/0030) co-funded by the Fondo Europeo de Desarrollo Regional (FEDER). R.C. acknowledges funding from MINECO (CTQ2016-78636-P). X.S. acknowledges funding from AGAUR (2017 SGR 324), Marató TV3 (102030), MINECO (BIO2012-31043 and BIO2015-70092-R), and the European Research Council (CONCERT, contract number 648201). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain)Peer reviewedSpringer NatureEuropean CommissionMinisterio de Economía y Competitividad (España)Crehuet, Ramón [0000-0002-6687-382X]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202020202019info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/200649reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/EC/H2020/653706info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/CTQ2016-78636-Pinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BIO2015-70092-Rinfo:eu-repo/grantAgreement/EC/H2020/648201https://doi.org/10.1038/s41467-019-09923-2Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2006492026-05-22T06:33:51Z
dc.title.none.fl_str_mv Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor
title Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor
spellingShingle Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor
Escobedo, Albert
Peptides
Mice
Huntington disease
HD Mouse
title_short Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor
title_full Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor
title_fullStr Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor
title_full_unstemmed Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor
title_sort Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor
dc.creator.none.fl_str_mv Escobedo, Albert
Topal, Busra
Kunze, Micha B.A.
Aranda, Juan
Chiesa, Giulio
Mungianu, Daniele
Bernardo-Seisdedos, Ganeko
Eftekharzadeh, Bahareh
Gairi, Margarida
Pierattelli, Roberta
Felli, Isabella Caterina
Diercks, Tammo
Millet, Oscar
García, Jesús
Orozco, Modesto
Crehuet, Ramón
Lindorff-Larsen, Kresten
Salvatella, Xavier
author Escobedo, Albert
author_facet Escobedo, Albert
Topal, Busra
Kunze, Micha B.A.
Aranda, Juan
Chiesa, Giulio
Mungianu, Daniele
Bernardo-Seisdedos, Ganeko
Eftekharzadeh, Bahareh
Gairi, Margarida
Pierattelli, Roberta
Felli, Isabella Caterina
Diercks, Tammo
Millet, Oscar
García, Jesús
Orozco, Modesto
Crehuet, Ramón
Lindorff-Larsen, Kresten
Salvatella, Xavier
author_role author
author2 Topal, Busra
Kunze, Micha B.A.
Aranda, Juan
Chiesa, Giulio
Mungianu, Daniele
Bernardo-Seisdedos, Ganeko
Eftekharzadeh, Bahareh
Gairi, Margarida
Pierattelli, Roberta
Felli, Isabella Caterina
Diercks, Tammo
Millet, Oscar
García, Jesús
Orozco, Modesto
Crehuet, Ramón
Lindorff-Larsen, Kresten
Salvatella, Xavier
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv European Commission
Ministerio de Economía y Competitividad (España)
Crehuet, Ramón [0000-0002-6687-382X]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Peptides
Mice
Huntington disease
HD Mouse
topic Peptides
Mice
Huntington disease
HD Mouse
description Polyglutamine (polyQ) tracts are regions of low sequence complexity frequently found in transcription factors. Tract length often correlates with transcriptional activity and expansion beyond specific thresholds in certain human proteins is the cause of polyQ disorders. To study the structural basis of the association between tract length, transcriptional activity and disease, we addressed how the conformation of the polyQ tract of the androgen receptor, associated with spinobulbar muscular atrophy (SBMA), depends on its length. Here we report that this sequence folds into a helical structure stabilized by unconventional hydrogen bonds between glutamine side chains and main chain carbonyl groups, and that its helicity directly correlates with tract length. These unusual hydrogen bonds are bifurcate with the conventional hydrogen bonds stabilizing α-helices. Our findings suggest a plausible rationale for the association between polyQ tract length and androgen receptor transcriptional activity and have implications for establishing the mechanistic basis of SBMA. © 2019, The Author(s).
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/200649
url http://hdl.handle.net/10261/200649
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/EC/H2020/653706
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/CTQ2016-78636-P
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BIO2015-70092-R
info:eu-repo/grantAgreement/EC/H2020/648201
https://doi.org/10.1038/s41467-019-09923-2
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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