The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8

Nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance pathway that regulates the degradation of mRNAs harboring premature translation termination codons. NMD also influences the expression of many physiological transcripts. SMG-1 is a large kinase essential to NMD that phosphorylates Upf1,...

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Autores: Arias-Palomo, Ernesto, Yamashita, Akio, Fernández, Israel S., Núñez-Ramírez, Rafael, Bamba, Yumi, Izumi, Natsuko, Ohno, Shigeo, Llorca, Óscar
Tipo de recurso: artículo
Fecha de publicación:2011
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/96710
Acceso en línea:http://hdl.handle.net/10261/96710
Access Level:acceso abierto
Palabra clave:NMD
Nonsense-mediated mRNA decay
SMG-9
SMG-1
SMG-8
Cryo-EM
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oai_identifier_str oai:digital.csic.es:10261/96710
network_acronym_str ES
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spelling The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8Arias-Palomo, ErnestoYamashita, AkioFernández, Israel S.Núñez-Ramírez, RafaelBamba, YumiIzumi, NatsukoOhno, ShigeoLlorca, ÓscarNMDNonsense-mediated mRNA decaySMG-9SMG-1SMG-8Cryo-EMNonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance pathway that regulates the degradation of mRNAs harboring premature translation termination codons. NMD also influences the expression of many physiological transcripts. SMG-1 is a large kinase essential to NMD that phosphorylates Upf1, which seems to be the definitive signal triggering mRNA decay. However, the regulation of the kinase activity of SMG-1 remains poorly understood. Here, we reveal the three-dimensional architecture of SMG-1 in complex with SMG-8 and SMG-9, and the structural mechanisms regulating SMG-1 kinase. A bent arm comprising a long region of HEAT (huntington, elongation factor 3, a subunit of PP2A and TOR1) repeats at the N terminus of SMG-1 functions as a scaffold for SMG-8 and SMG-9, and projects from the C-terminal core containing the phosphatidylinositol 3-kinase domain. SMG-9 seems to control the activity of SMG-1 indirectly through the recruitment of SMG-8 to the N-terminal HEAT repeat region of SMG-1. Notably, SMG-8 binding to the SMG-1:SMG-9 complex specifically down-regulates the kinase activity of SMG-1 on Upf1 without contacting the catalytic domain. Assembly of the SMG-1:SMG-8:SMG-9 complex induces a significant motion of the HEAT repeats that is signaled to the kinase domain. Thus, large-scale conformational changes induced by SMG-8 after SMG-9-mediated recruitment tune SMG-1 kinase activity to modulate NMD. © 2011 by Cold Spring Harbor Laboratory Press.This work was funded by the Spanish Ministry of Science and Innovation (SAF2008-00451 to O.L.); the Red Temática de Investigación Cooperativa en Cáncer (RTICC) from the Instituto de Salud Carlos III (RD06/0020/1001 to O.L.); the Autonomous Region of Madrid (CAM S-BIO-0214-2006 to O.L.); the Human Frontiers Science Program (RGP39/2008 to O.L.); the Consejería de Educación de la Comunidad de Madrid y Fondo Social Europeo (to E.A.P.); the Japan Society for the Promotion of Science (to A.Y. and S.O.); the Japan Science and Technology Corporation (to A.Y. and S.O.); the Ministry of Education,Culture, Sports, Science, and Technology of Japan (to S.O.); the Takeda Science Foundation (to S.O.); and the Yokohama Foundation for Advancement of Medical Science (to A.Y.).Peer ReviewedCold Spring Harbor Laboratory Press2014201420112014info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501http://hdl.handle.net/10261/96710reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1101/gad.606911info:eu-repo/semantics/openAccessoai:digital.csic.es:10261/967102026-05-22T06:33:51Z
dc.title.none.fl_str_mv The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8
title The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8
spellingShingle The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8
Arias-Palomo, Ernesto
NMD
Nonsense-mediated mRNA decay
SMG-9
SMG-1
SMG-8
Cryo-EM
title_short The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8
title_full The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8
title_fullStr The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8
title_full_unstemmed The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8
title_sort The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8
dc.creator.none.fl_str_mv Arias-Palomo, Ernesto
Yamashita, Akio
Fernández, Israel S.
Núñez-Ramírez, Rafael
Bamba, Yumi
Izumi, Natsuko
Ohno, Shigeo
Llorca, Óscar
author Arias-Palomo, Ernesto
author_facet Arias-Palomo, Ernesto
Yamashita, Akio
Fernández, Israel S.
Núñez-Ramírez, Rafael
Bamba, Yumi
Izumi, Natsuko
Ohno, Shigeo
Llorca, Óscar
author_role author
author2 Yamashita, Akio
Fernández, Israel S.
Núñez-Ramírez, Rafael
Bamba, Yumi
Izumi, Natsuko
Ohno, Shigeo
Llorca, Óscar
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv NMD
Nonsense-mediated mRNA decay
SMG-9
SMG-1
SMG-8
Cryo-EM
topic NMD
Nonsense-mediated mRNA decay
SMG-9
SMG-1
SMG-8
Cryo-EM
description Nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance pathway that regulates the degradation of mRNAs harboring premature translation termination codons. NMD also influences the expression of many physiological transcripts. SMG-1 is a large kinase essential to NMD that phosphorylates Upf1, which seems to be the definitive signal triggering mRNA decay. However, the regulation of the kinase activity of SMG-1 remains poorly understood. Here, we reveal the three-dimensional architecture of SMG-1 in complex with SMG-8 and SMG-9, and the structural mechanisms regulating SMG-1 kinase. A bent arm comprising a long region of HEAT (huntington, elongation factor 3, a subunit of PP2A and TOR1) repeats at the N terminus of SMG-1 functions as a scaffold for SMG-8 and SMG-9, and projects from the C-terminal core containing the phosphatidylinositol 3-kinase domain. SMG-9 seems to control the activity of SMG-1 indirectly through the recruitment of SMG-8 to the N-terminal HEAT repeat region of SMG-1. Notably, SMG-8 binding to the SMG-1:SMG-9 complex specifically down-regulates the kinase activity of SMG-1 on Upf1 without contacting the catalytic domain. Assembly of the SMG-1:SMG-8:SMG-9 complex induces a significant motion of the HEAT repeats that is signaled to the kinase domain. Thus, large-scale conformational changes induced by SMG-8 after SMG-9-mediated recruitment tune SMG-1 kinase activity to modulate NMD. © 2011 by Cold Spring Harbor Laboratory Press.
publishDate 2011
dc.date.none.fl_str_mv 2011
2014
2014
2014
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/96710
url http://hdl.handle.net/10261/96710
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1101/gad.606911
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Cold Spring Harbor Laboratory Press
publisher.none.fl_str_mv Cold Spring Harbor Laboratory Press
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
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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