Structural characterization of PPAR³:SIRT1 protein complex in the context of obesity and insulin resistance

Abstract

Metabolic syndrome is a cluster of conditions that happens simultaneously within the body and may lead to clinical conditions such as obesity and type II diabetes. This work focus on the structural investigation of the deacetylase SIRT1 and the nuclear receptor PPAR³, a master regulator of adipogenesis and glucose homeostasis. Recently studies demonstrate that PPAR³ controls adipogenesis through deacetylation of Lys268 and Lys293 by SIRT1. However, little is known about the mechanism behind SIRT1 and PPAR³ complex formation. Then, we aim to (1) identify residue/interfaces involved in complex formation and (2) its modulation by well-known PPAR³ and SIRT1 ligands. Additionally, recent studies from our group demonstrate negative crosstalk between the PPAR³ post-translational modification (PTM): the insulin-sensitivity Lys268 and Lys293 acetylation/deacetylation and the insulin-resistant Ser273 phosphorylation. Thus, we also intend to (3) study the influence of Ser273 phosphorylation on SIRT1:PPAR³ complex formation. For that, we choose Hydrogen-deuterium exchange mass spectrometry as a primary tool to accomplish all the goals of this project. The investigation of PTMs influence on PPAR³ activity and its interaction with SIRT1 sets a new approach for drug discovery for treating insulin resistance and obesity. (AU)