Abstract
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 PPARγ and RXRα 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 hPPARγ 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, hPPARγ remains in the monomeric form by itself but forms heterodimers with hRXRα. The low-resolution models of hPPARγ/RXRα 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.
Highlights
Peroxisome proliferators activated receptors (PPARs) are members of the nuclear receptor (NR) family, acting as liganddependent transcription factors and modulating the activation of cognate genes
The proteins were submitted to SDSPAGE (Figure S1), native electrophoresis (Figure S2) and dynamic light scattering experiments (Figure S3) confirming the previous values found to RH and apparent molecular weight (Table 1)
PPARc has a central role in the regulation of glucose and lipid homeostasis and is involved in inflammatory processes and is an important drug target for treatment of Type 2 Diabetes and inflammation [28,29]
Summary
Peroxisome proliferators activated receptors (PPARs) are members of the nuclear receptor (NR) family, acting as liganddependent transcription factors and modulating the activation of cognate genes. PPARc plays a central role in the glucose regulation, lipid homeostasis and in the control of the energy balance. Because of this, it has been extensively studied as a molecular target in type II diabetes treatment [1]. PPARs, like other nuclear receptors, are modular proteins composed of several separable domains [4]. Their N-terminal region (A/B) harbors a ligand-independent activation function 1 (AF-1). The conserved C region corresponds to the DNA binding domain (DBD) and is responsible for sequence-specific DNA recognition. A highly structured E region, or ligand-binding domain (LBD), is responsible for ligand specificity and co-factors recruitment. Hinge or D region is located between C and E domains and is the target of functionally relevant post-translational modifications like phosphorylation and sumoylation [4] (Figure 1)
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