Low-Resolution Molecular Models Reveal the Oligomeric State of the PPAR and the Conformational Organization of Its Domains in Solution

Autor(es)

Bernardes, Amanda ^[1] ; Batista, Fernanda A. H. ^[1] ; Neto, Mario de Oliveira ^[1] ; Figueira, Ana Carolina M. ^[2] ; Webb, Paul ^{[3, 4]} ; Saidemberg, Daniel ^{[5, 6]} ; Palma, Mario S. ^{[5, 6]} ; Polikarpov, Igor ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Phys Sao Carlos, Sao Paulo - Brazil

^[2] CNPEM, Natl Lab Biosci, Sao Paulo - Brazil

^[3] Methodist Hosp, Ctr Diabet, Houston, TX 77030 - USA

^[4] Methodist Hosp, Canc Res Unit, Houston, TX 77030 - USA

^[5] Univ Estadual Sao Paulo UNESP, Inst Biosci Rio Claro, Dept Biol, Ctr Study Social Insects CEIS, Sao Paulo - Brazil

^[6] Natl Inst Sci & Technol Immunol INCT Iii, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 7, n. 2 FEB 21 2012.
• Citações Web of Science: 12

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. (AU)

• Processo FAPESP: 06/00182-8 - Biofísica estrutural dos receptores nucleares e proteínas relacionadas
• Beneficiário: Igor Polikarpov
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 10/17048-8 - Regulação da transativação e transrepressão gênica mediada por receptores nucleares
• Beneficiário: Ana Carolina Migliorini Figueira
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 08/00078-1 - Estudos estruturais e biofísicos de complexos formados entre receptores nucleares, seus ligantes, elementos responsivos de DNA e proteínas co-reguladoras
• Beneficiário: Ana Carolina Migliorini Figueira
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 07/58443-4 - Estudos estruturais e funcionais dos receptores ativadores da proliferação de peroxissomos
• Beneficiário: Amanda Bernardes Muniz
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 08/05637-9 - Estudos dos três isotipos do receptor ativador de proliferação de peroxissomos (hPPAR) e da interação destes com receptor de retinoides X hRXRalfa em solução usando espalhamento de raios-X a baixo ângulo
• Beneficiário: Mario de Oliveira Neto
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado