Influence of structural modifications caused by the phosphorylation of the Ser273 of the PPAR³ in the recruitment of correpressors and in the formation of the RXR-PPAR³ heterodimer

Abstract

Obesity and metabolic syndrome are global epidemics that tend to grow. In these conditions the transcription of several genes is altered, including that of adiponectin, a protein responsible for a set of metabolic regulations that result in the sensitization of the organism to insulin, whose expression is decreased in obese individuals, being that the main factor for the development of diabetes mellitus type 2. The PPAR³ is a nuclear receptor, directly influencing the activation or repression of genes through its association with coactivators and various corepressors, responsible for recruiting chromatin modulating enzymes. Due to its involvement in the expression of adiponectin, PPAR³ is a molecular target for the development of novel insulin sensitization therapies. The discovery of the phosphorylation of PPAR³ by the CDK5 kinase has long been thought to be the main cause of repression of this nuclear receptor, however, it is now assumed that phosphorylation acts on the recruitment of corepressors, rather than directly inhibiting the activation of PPAR³. Therefore, the study of the interactions and the structure of the molecules involved in this process are of great importance for the development of new insulin sensitizing drugs without activating the PPAR³ as it happens with the current drugs, known to cause several side effects. Thus, this project aims to study the structural mechanisms involved in the phosphorylation of PPAR³ and its consequences for the formation of the PPAR³-RXR heterodimer and for the differential recruitment of corepressors through phosphorylation, biophysical and structural assays for these molecules. (AU)