Low-Resolution Molecular Models Reveal the Oligomeric State of the PPAR and the Conformational Organization of Its Domains in Solution
Autor(a) principal: | |
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Data de Publicação: | 2012 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1371/journal.pone.0031852 http://hdl.handle.net/11449/20012 |
Resumo: | The peroxisome proliferator-activated receptors (PPARs) regulate genes involved in lipid and carbohydrate metabolism, and are targets of drugs approved for human use. Whereas the crystallographic structure of the complex of full length PPAR gamma and RXR alpha is known, structural alterations induced by heterodimer formation and DNA contacts are not well understood. Herein, we report a small-angle X-ray scattering analysis of the oligomeric state of hPPAR gamma alone and in the presence of retinoid X receptor (RXR). The results reveal that, in contrast with other studied nuclear receptors, which predominantly form dimers in solution, hPPAR gamma remains in the monomeric form by itself but forms heterodimers with hRXR alpha. The low-resolution models of hPPAR gamma/RXR alpha complexes predict significant changes in opening angle between heterodimerization partners (LBD) and extended and asymmetric shape of the dimer (LBD-DBD) as compared with X-ray structure of the full-length receptor bound to DNA. These differences between our SAXS models and the high-resolution crystallographic structure might suggest that there are different conformations of functional heterodimer complex in solution. Accordingly, hydrogen/deuterium exchange experiments reveal that the heterodimer binding to DNA promotes more compact and less solvent-accessible conformation of the receptor complex. |
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Low-Resolution Molecular Models Reveal the Oligomeric State of the PPAR and the Conformational Organization of Its Domains in SolutionThe peroxisome proliferator-activated receptors (PPARs) regulate genes involved in lipid and carbohydrate metabolism, and are targets of drugs approved for human use. Whereas the crystallographic structure of the complex of full length PPAR gamma and RXR alpha is known, structural alterations induced by heterodimer formation and DNA contacts are not well understood. Herein, we report a small-angle X-ray scattering analysis of the oligomeric state of hPPAR gamma alone and in the presence of retinoid X receptor (RXR). The results reveal that, in contrast with other studied nuclear receptors, which predominantly form dimers in solution, hPPAR gamma remains in the monomeric form by itself but forms heterodimers with hRXR alpha. The low-resolution models of hPPAR gamma/RXR alpha complexes predict significant changes in opening angle between heterodimerization partners (LBD) and extended and asymmetric shape of the dimer (LBD-DBD) as compared with X-ray structure of the full-length receptor bound to DNA. These differences between our SAXS models and the high-resolution crystallographic structure might suggest that there are different conformations of functional heterodimer complex in solution. Accordingly, hydrogen/deuterium exchange experiments reveal that the heterodimer binding to DNA promotes more compact and less solvent-accessible conformation of the receptor complex.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ São Paulo, Inst Phys Sao Carlos, São Paulo, BrazilCNPEM, Natl Lab Biosci, São Paulo, BrazilMethodist Hosp, Ctr Diabet, Houston, TX 77030 USAMethodist Hosp, Canc Res Unit, Houston, TX 77030 USAUniv Estadual São Paulo UNESP, Inst Biosci Rio Claro, Dept Biol, Ctr Study Social Insects CEIS, São Paulo, BrazilNatl Inst Sci & Technol Immunol INCT Iii, São Paulo, BrazilUniv Estadual São Paulo UNESP, Inst Biosci Rio Claro, Dept Biol, Ctr Study Social Insects CEIS, São Paulo, BrazilFAPESP: 06/00182-8FAPESP: 07/58443-4FAPESP: 08/05637-9FAPESP: 08/00078-1FAPESP: 10/17048-8Public Library ScienceUniversidade de São Paulo (USP)Centro Nacional de Pesquisa em Energia e Materiais (CNPEM)Houston Methodist HospitalUniversidade Estadual Paulista (Unesp)Instituto de Investigação em Imunologia - Instituto Nacional de Ciência e Tecnologia (INCT)Bernardes, AmandaBatista, Fernanda A. H.Neto, Mario de OliveiraFigueira, Ana Carolina M.Webb, PaulSaidemberg, Daniel [UNESP]Palma, Mario Sergio [UNESP]Polikarpov, Igor2014-05-20T13:55:54Z2014-05-20T13:55:54Z2012-02-21info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article15application/pdfhttp://dx.doi.org/10.1371/journal.pone.0031852Plos One. San Francisco: Public Library Science, v. 7, n. 2, p. 15, 2012.1932-6203http://hdl.handle.net/11449/2001210.1371/journal.pone.0031852WOS:000302873700108WOS000302873700108.pdf29018886245065358213371495151651Web of Sciencereponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengPLOS ONE2.7661,164info:eu-repo/semantics/openAccess2024-01-25T06:33:24Zoai:repositorio.unesp.br:11449/20012Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T23:57:52.107961Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Low-Resolution Molecular Models Reveal the Oligomeric State of the PPAR and the Conformational Organization of Its Domains in Solution |
title |
Low-Resolution Molecular Models Reveal the Oligomeric State of the PPAR and the Conformational Organization of Its Domains in Solution |
spellingShingle |
Low-Resolution Molecular Models Reveal the Oligomeric State of the PPAR and the Conformational Organization of Its Domains in Solution Bernardes, Amanda |
title_short |
Low-Resolution Molecular Models Reveal the Oligomeric State of the PPAR and the Conformational Organization of Its Domains in Solution |
title_full |
Low-Resolution Molecular Models Reveal the Oligomeric State of the PPAR and the Conformational Organization of Its Domains in Solution |
title_fullStr |
Low-Resolution Molecular Models Reveal the Oligomeric State of the PPAR and the Conformational Organization of Its Domains in Solution |
title_full_unstemmed |
Low-Resolution Molecular Models Reveal the Oligomeric State of the PPAR and the Conformational Organization of Its Domains in Solution |
title_sort |
Low-Resolution Molecular Models Reveal the Oligomeric State of the PPAR and the Conformational Organization of Its Domains in Solution |
author |
Bernardes, Amanda |
author_facet |
Bernardes, Amanda Batista, Fernanda A. H. Neto, Mario de Oliveira Figueira, Ana Carolina M. Webb, Paul Saidemberg, Daniel [UNESP] Palma, Mario Sergio [UNESP] Polikarpov, Igor |
author_role |
author |
author2 |
Batista, Fernanda A. H. Neto, Mario de Oliveira Figueira, Ana Carolina M. Webb, Paul Saidemberg, Daniel [UNESP] Palma, Mario Sergio [UNESP] Polikarpov, Igor |
author2_role |
author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade de São Paulo (USP) Centro Nacional de Pesquisa em Energia e Materiais (CNPEM) Houston Methodist Hospital Universidade Estadual Paulista (Unesp) Instituto de Investigação em Imunologia - Instituto Nacional de Ciência e Tecnologia (INCT) |
dc.contributor.author.fl_str_mv |
Bernardes, Amanda Batista, Fernanda A. H. Neto, Mario de Oliveira Figueira, Ana Carolina M. Webb, Paul Saidemberg, Daniel [UNESP] Palma, Mario Sergio [UNESP] Polikarpov, Igor |
description |
The peroxisome proliferator-activated receptors (PPARs) regulate genes involved in lipid and carbohydrate metabolism, and are targets of drugs approved for human use. Whereas the crystallographic structure of the complex of full length PPAR gamma and RXR alpha is known, structural alterations induced by heterodimer formation and DNA contacts are not well understood. Herein, we report a small-angle X-ray scattering analysis of the oligomeric state of hPPAR gamma alone and in the presence of retinoid X receptor (RXR). The results reveal that, in contrast with other studied nuclear receptors, which predominantly form dimers in solution, hPPAR gamma remains in the monomeric form by itself but forms heterodimers with hRXR alpha. The low-resolution models of hPPAR gamma/RXR alpha complexes predict significant changes in opening angle between heterodimerization partners (LBD) and extended and asymmetric shape of the dimer (LBD-DBD) as compared with X-ray structure of the full-length receptor bound to DNA. These differences between our SAXS models and the high-resolution crystallographic structure might suggest that there are different conformations of functional heterodimer complex in solution. Accordingly, hydrogen/deuterium exchange experiments reveal that the heterodimer binding to DNA promotes more compact and less solvent-accessible conformation of the receptor complex. |
publishDate |
2012 |
dc.date.none.fl_str_mv |
2012-02-21 2014-05-20T13:55:54Z 2014-05-20T13:55:54Z |
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/10.1371/journal.pone.0031852 Plos One. San Francisco: Public Library Science, v. 7, n. 2, p. 15, 2012. 1932-6203 http://hdl.handle.net/11449/20012 10.1371/journal.pone.0031852 WOS:000302873700108 WOS000302873700108.pdf 2901888624506535 8213371495151651 |
url |
http://dx.doi.org/10.1371/journal.pone.0031852 http://hdl.handle.net/11449/20012 |
identifier_str_mv |
Plos One. San Francisco: Public Library Science, v. 7, n. 2, p. 15, 2012. 1932-6203 10.1371/journal.pone.0031852 WOS:000302873700108 WOS000302873700108.pdf 2901888624506535 8213371495151651 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
PLOS ONE 2.766 1,164 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
15 application/pdf |
dc.publisher.none.fl_str_mv |
Public Library Science |
publisher.none.fl_str_mv |
Public Library Science |
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Web of Science reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
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Universidade Estadual Paulista (UNESP) |
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UNESP |
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UNESP |
reponame_str |
Repositório Institucional da UNESP |
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Repositório Institucional da UNESP |
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Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
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