| Texto completo | |
| Autor(es): |
Malospirito, Caique Camargo
;
Jara, Gabriel Ernesto
;
Antunes, Victor Ulian
;
Elias, Giovanna Blazutti
;
Dias, Marieli Mariano Goncalves
;
Batista, Fernanda Aparecida Heleno
;
de Oliveira, Paulo Sergio Lopes
;
Figueira, Ana Carolina Migliorini
Número total de Autores: 8
|
| Tipo de documento: | Artigo Científico |
| Fonte: | PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS; v. N/A, p. 15-pg., 2025-07-17. |
| Resumo | |
Insulin resistance, a global health threat linked to type 2 diabetes and obesity, can be addressed by modulating the activity of the Sirtuin 1 (SIRT1), a deacetylase that enhances insulin sensitivity by deacetylating the Peroxisome Proliferator-Activated Receptor Gamma (PPAR gamma) at lysine 268 and 293. Understanding the binding interfaces between SIRT1 and PPAR gamma is critical to developing new strategies to combat insulin resistance. In this study, we present four experimentally supported binding models of SIRT1 with acetylated PPAR gamma: one at position 268 and three at position 293 (SIRT1-K268PPAR gamma and SIRT1-K293PPAR gamma 1-3 models). These models were generated through an integration of in silico modeling and in vitro binding affinity assays. Our models revealed that the SIRT1:PPAR gamma binding interface is structured by SIRT1's 3-helix bundle in N-terminus domain (NTD(3HB)) and the catalytic domain (CD). The CD accommodated the acetylated peptide in its active site, while NTD(3HB) anchors PPAR gamma at a region between loops alpha 1-beta 1 and alpha 2 '-alpha 3 within PPAR gamma's ligand binding domain (LBD). Notably, the SIRT1-NTD(3HB) consistently bound to the same region of PPAR gamma in both models, highlighting a common mode for interaction. Through molecular dynamic simulation and binding assays, we demonstrated that either removal of SIRT1-NTD(3HB) or mutation within PPAR gamma-LBD significantly reduces binding affinity, underscoring the role of NTD(3HB) in substrate anchoring. Additionally, we provided evidence of SIRT1 dimerization, with substrate binding inducing its dissociation to form a heterodimer with PPAR gamma. These findings underscore the importance of the SIRT1 NTD(3HB) in PPAR gamma anchoring and offer insights into the activation mechanism of SIRT1, with potential implications for drug development targeting insulin resistance. (AU) | |
| Processo FAPESP: | 20/08366-8 - Caracterização das bases moleculares da interação do receptor nuclear PPAR³ com a desacetilase SIRT1 sob a influência da fosforilação do receptor no contexto na regulação da homeostase metabólica |
| Beneficiário: | Caique Camargo Malospirito |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado |
| Processo FAPESP: | 22/11485-4 - Construção de um modelo microfisiológico de cultura de fígado 3D esteatótica induzida por culturas 3D de tecido adiposo obeso e modulação de vias relacionadas ao PPAR³ |
| Beneficiário: | Ana Carolina Migliorini Figueira |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |