DNA mismatch repair proteins MLH1 and PMS2 can be imported to the nucleus by a classical nuclear import pathway
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1016/j.biochi.2017.11.013 http://hdl.handle.net/11449/163868 |
Resumo: | MLH1 and PMS2 proteins form the MutLa heterodimer, which plays a major role in DNA mismatch repair (MMR) in humans. Mutations in MMR-related proteins are associated with cancer, especially with colon cancer. The N-terminal region of MutLa comprises the N-termini of PMS2 and MLH1 and, similarly, the C-terminal region of MutLa is composed by the C-termini of PMS2 and MLH1, and the two are connected by linker region. The nuclear localization sequences (NLSs) necessary for the nuclear transport of the two proteins are found in this linker region. However, the exact NLS sequences have been controversial, with different sequences reported, particularly for MLH1. The individual components are not imported efficiently, presumably due to their C-termini masking their NLSs. In order to gain insights into the nuclear transport of these proteins, we solved the crystal structures of importin-alpha bound to peptides corresponding to the supposed NLSs of MLH1 and PMS2 and performed isothermal titration calorimetry to study their binding affinities. Both putative MLH1 and PMS2 NLSs can bind to importin-alpha as monopartite NLSs, which is in agreement with some previous studies. However, MLH1-NLS has the highest affinity measured by a natural NLS peptide, suggesting a major role of MLH1 protein in nuclear import compared to PMS2. Finally, the role of MLH1 and PMS2 in the nuclear transport of the MutLa heterodimer is discussed. (C) 2017 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved. |
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DNA mismatch repair proteins MLH1 and PMS2 can be imported to the nucleus by a classical nuclear import pathwayImportin-alphaNuclear import pathwayNuclear localization sequence (NLS)DNA repairMLH1 and PMS2 proteinsX-ray crystallographyIsothermal titration calorimetryMLH1 and PMS2 proteins form the MutLa heterodimer, which plays a major role in DNA mismatch repair (MMR) in humans. Mutations in MMR-related proteins are associated with cancer, especially with colon cancer. The N-terminal region of MutLa comprises the N-termini of PMS2 and MLH1 and, similarly, the C-terminal region of MutLa is composed by the C-termini of PMS2 and MLH1, and the two are connected by linker region. The nuclear localization sequences (NLSs) necessary for the nuclear transport of the two proteins are found in this linker region. However, the exact NLS sequences have been controversial, with different sequences reported, particularly for MLH1. The individual components are not imported efficiently, presumably due to their C-termini masking their NLSs. In order to gain insights into the nuclear transport of these proteins, we solved the crystal structures of importin-alpha bound to peptides corresponding to the supposed NLSs of MLH1 and PMS2 and performed isothermal titration calorimetry to study their binding affinities. Both putative MLH1 and PMS2 NLSs can bind to importin-alpha as monopartite NLSs, which is in agreement with some previous studies. However, MLH1-NLS has the highest affinity measured by a natural NLS peptide, suggesting a major role of MLH1 protein in nuclear import compared to PMS2. Finally, the role of MLH1 and PMS2 in the nuclear transport of the MutLa heterodimer is discussed. (C) 2017 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Spanish Ministerio de Economia y CompetitividadUniv Estadual Paulista, Inst Biociencias, Dept Fis & Biofis, BR-18618689 Botucatu, SP, BrazilUniv Zaragoza, Joint Unit IQFR CSIC BIFI, Inst Biocomputat & Phys Complex Syst BIFI, Zaragoza, SpainUniv Zaragoza, Dep Biochem & Mol & Cell Biol, Zaragoza, SpainGovt Aragon, Fdn ARAID, Zaragoza, SpainUniv Queensland, Sch Chem & Mol Biosci, Inst Mol Biosci, Brisbane, Qld 4072, AustraliaUniv Queensland, Australian Infect Dis Res Ctr, Brisbane, Qld 4072, AustraliaUniv Estadual Paulista, Inst Biociencias, Dept Fis & Biofis, BR-18618689 Botucatu, SP, BrazilFAPESP: 2013/24705-3FAPESP: 2009/14118-8Spanish Ministerio de Economia y Competitividad: BFU2016-78232-PElsevier B.V.Universidade Estadual Paulista (Unesp)Univ ZaragozaGovt AragonUniv QueenslandBarros, Andrea C. de [UNESP]Takeda, Agnes A. S. [UNESP]Dreyer, Thiago R. [UNESP]Velazquez-Campoy, AdrianKobe, BostjanFontes, Marcos R. M. [UNESP]2018-11-26T17:48:14Z2018-11-26T17:48:14Z2018-03-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article87-96application/pdfhttp://dx.doi.org/10.1016/j.biochi.2017.11.013Biochimie. Issy-les-moulineaux: Elsevier France-editions Scientifiques Medicales Elsevier, v. 146, p. 87-96, 2018.0300-9084http://hdl.handle.net/11449/16386810.1016/j.biochi.2017.11.013WOS:000425283600011WOS000425283600011.pdfWeb of Sciencereponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengBiochimie1,554info:eu-repo/semantics/openAccess2024-01-27T06:59:03Zoai:repositorio.unesp.br:11449/163868Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-06T00:06:08.578113Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
DNA mismatch repair proteins MLH1 and PMS2 can be imported to the nucleus by a classical nuclear import pathway |
title |
DNA mismatch repair proteins MLH1 and PMS2 can be imported to the nucleus by a classical nuclear import pathway |
spellingShingle |
DNA mismatch repair proteins MLH1 and PMS2 can be imported to the nucleus by a classical nuclear import pathway Barros, Andrea C. de [UNESP] Importin-alpha Nuclear import pathway Nuclear localization sequence (NLS) DNA repair MLH1 and PMS2 proteins X-ray crystallography Isothermal titration calorimetry |
title_short |
DNA mismatch repair proteins MLH1 and PMS2 can be imported to the nucleus by a classical nuclear import pathway |
title_full |
DNA mismatch repair proteins MLH1 and PMS2 can be imported to the nucleus by a classical nuclear import pathway |
title_fullStr |
DNA mismatch repair proteins MLH1 and PMS2 can be imported to the nucleus by a classical nuclear import pathway |
title_full_unstemmed |
DNA mismatch repair proteins MLH1 and PMS2 can be imported to the nucleus by a classical nuclear import pathway |
title_sort |
DNA mismatch repair proteins MLH1 and PMS2 can be imported to the nucleus by a classical nuclear import pathway |
author |
Barros, Andrea C. de [UNESP] |
author_facet |
Barros, Andrea C. de [UNESP] Takeda, Agnes A. S. [UNESP] Dreyer, Thiago R. [UNESP] Velazquez-Campoy, Adrian Kobe, Bostjan Fontes, Marcos R. M. [UNESP] |
author_role |
author |
author2 |
Takeda, Agnes A. S. [UNESP] Dreyer, Thiago R. [UNESP] Velazquez-Campoy, Adrian Kobe, Bostjan Fontes, Marcos R. M. [UNESP] |
author2_role |
author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (Unesp) Univ Zaragoza Govt Aragon Univ Queensland |
dc.contributor.author.fl_str_mv |
Barros, Andrea C. de [UNESP] Takeda, Agnes A. S. [UNESP] Dreyer, Thiago R. [UNESP] Velazquez-Campoy, Adrian Kobe, Bostjan Fontes, Marcos R. M. [UNESP] |
dc.subject.por.fl_str_mv |
Importin-alpha Nuclear import pathway Nuclear localization sequence (NLS) DNA repair MLH1 and PMS2 proteins X-ray crystallography Isothermal titration calorimetry |
topic |
Importin-alpha Nuclear import pathway Nuclear localization sequence (NLS) DNA repair MLH1 and PMS2 proteins X-ray crystallography Isothermal titration calorimetry |
description |
MLH1 and PMS2 proteins form the MutLa heterodimer, which plays a major role in DNA mismatch repair (MMR) in humans. Mutations in MMR-related proteins are associated with cancer, especially with colon cancer. The N-terminal region of MutLa comprises the N-termini of PMS2 and MLH1 and, similarly, the C-terminal region of MutLa is composed by the C-termini of PMS2 and MLH1, and the two are connected by linker region. The nuclear localization sequences (NLSs) necessary for the nuclear transport of the two proteins are found in this linker region. However, the exact NLS sequences have been controversial, with different sequences reported, particularly for MLH1. The individual components are not imported efficiently, presumably due to their C-termini masking their NLSs. In order to gain insights into the nuclear transport of these proteins, we solved the crystal structures of importin-alpha bound to peptides corresponding to the supposed NLSs of MLH1 and PMS2 and performed isothermal titration calorimetry to study their binding affinities. Both putative MLH1 and PMS2 NLSs can bind to importin-alpha as monopartite NLSs, which is in agreement with some previous studies. However, MLH1-NLS has the highest affinity measured by a natural NLS peptide, suggesting a major role of MLH1 protein in nuclear import compared to PMS2. Finally, the role of MLH1 and PMS2 in the nuclear transport of the MutLa heterodimer is discussed. (C) 2017 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-11-26T17:48:14Z 2018-11-26T17:48:14Z 2018-03-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1016/j.biochi.2017.11.013 Biochimie. Issy-les-moulineaux: Elsevier France-editions Scientifiques Medicales Elsevier, v. 146, p. 87-96, 2018. 0300-9084 http://hdl.handle.net/11449/163868 10.1016/j.biochi.2017.11.013 WOS:000425283600011 WOS000425283600011.pdf |
url |
http://dx.doi.org/10.1016/j.biochi.2017.11.013 http://hdl.handle.net/11449/163868 |
identifier_str_mv |
Biochimie. Issy-les-moulineaux: Elsevier France-editions Scientifiques Medicales Elsevier, v. 146, p. 87-96, 2018. 0300-9084 10.1016/j.biochi.2017.11.013 WOS:000425283600011 WOS000425283600011.pdf |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Biochimie 1,554 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
87-96 application/pdf |
dc.publisher.none.fl_str_mv |
Elsevier B.V. |
publisher.none.fl_str_mv |
Elsevier B.V. |
dc.source.none.fl_str_mv |
Web of Science reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1808129583298379776 |