Structural studies of the three isotypes of the peroxisomal proliferator-activated receptor hPPAR and them interaction with retinoid receptor hRXRalfa using small angle X-ray scattering

Abstract

Nuclear receptors are of paramount importance to the processes of intercellular signaling in eukaryotes, since they have the ability to converge various internal and external signals important for the regulation of genetic programs involved in all aspects of the multicellular organism's life, such as: embryogenesis, homeostasis, reproduction, growth and cell death. The transcriptional regulation and selectivity promoted by these proteins have fostered intense research with the objective to unveil the complex network of molecular events that describe their way of action. Now a day, the full knowledge of the rules that promote the spatial and temporal control of gene expression by the nuclear receptors is still an important challenge. In this context, we propose as the main objective of this project to carry out SAXS studies of the interactions of the three isotypes of the Peroxisome Proliferator-Activated Receptor (PPAR) with isoform alfa of the 9-cis Retinoic Acid Receptor (hRXRalfa). Different constructs of PPAR isotypes and RXR will be analyzed, such as: the full-length protein, constructs containing both DNA binding domain (DBD) and ligand binding domain (LBD), and constructs with only the ligand binding domain (LBD). We hope that the results will enable us to determine the spatial position of the different domains present in the full-length nuclear receptors; as well as, to verify conformational changes, if they exist, when proteins are exposed to their ligands, cofactors, responsive elements, or to other elements of the superfamily. (AU)