Figure 8.

Interaction of PPAR-γ with coactivators and corepressors. PPAR-γ heteromerizes with RXR-α in a ligand-dependent manner (small blue circle inside the RXR-α molecule) in the cell nucleus. Although the preactivation of RXR-α occurs in a PPAR-γ-independent manner, it contributes to the transcriptional activity of the heterodimer. On the other hand, full transcriptional activation typically requires both RXR-α and PPAR-γ to be activated, as these receptors work cooperatively within the heterodimer. (a) As a part of the heterodimer, PPAR-γ interacts with an agonist (small green circle inside the PPAR-γ molecule) to form an agonist–receptor complex (AgRC). This interaction stabilizes PPAR-γ in the “open” conformation, favoring the recruitment of coactivators. Specifically, it creates a docking site for PGC1-α. (b) The binding of PGC1-α leads to additional structural rearrangements in PPAR-γ. (c) When in the nucleus, PPAR-γ recruits NCoA. (d) Then, the protein complex binds to histone acetyltransferases (p300 and CBP), which remodel chromatin and facilitate PPAR-γ binding to PPAR-γ responsive elements (PPREs). (e) Binding to an antagonist (small red square inside the PPAR-γ molecule) leads to the formation of antagonist–receptor complex (AnRC) and stabilizes PPAR-γ in the “closed” conformation. This interaction prevents the recruitment of coactivators to PPAR-γ and facilitates its interaction with corepressors. (f) If the antagonist binding is reversible, PPAR-γ may exchange the antagonist for an agonist and switch back to the “open” conformation. (g) Moreover, PPAR-γ may interact with corepressors (NCoR or SMRT) that exhibit deacetylase activity, remodeling chromatin and preventing DNA-dependent RNA polymerase II from recognizing PPREs and transcribing PPAR-γ target genes. (h) Irreversible modification of the agonist binding site by an antagonist locks PPAR-γ in the “closed” conformation, preventing exchange with an agonist and subsequent activation of PPAR-γ.