The Asymmetric Binding of PGC-1α to the ERRα and ERRγ Nuclear Receptor Homodimers Involves a Similar Recognition Mechanism

Background: PGC-1 alpha is a crucial regulator of cellular metabolism and energy homeostasis that functionally acts together with the estrogen-related receptors (ERR alpha and ERR gamma) in the regulation of mitochondrial and metabolic gene networks. Dimerization of the ERRs is a pre-requisite for interactions with PGC-1 alpha and other coactivators, eventually leading to transactivation. It was suggested recently (Devarakonda et al) that PGC-1 alpha binds in a strikingly different manner to ERR gamma ligand-binding domains (LBDs) compared to its mode of binding to ERR alpha and other nuclear receptors (NRs), where it interacts directly with the two ERR gamma homodimer subunits. Methods/Principal Findings: Here, we show that PGC-1 alpha receptor interacting domain (RID) binds in an almost identical manner to ERR alpha and ERR gamma homodimers. Microscale thermophoresis demonstrated that the interactions between PGC-1 alpha RID and ERR LBDs involve a single receptor subunit through high-affinity, ERR-specific L3 and low-affinity L2 interactions. NMR studies further defined the limits of PGC-1 alpha RID that interacts with ERRs. Consistent with these findings, the solution structures of PGC-1 alpha/ERRa LBDs and PGC-1 alpha/ERRc LBDs complexes share an identical architecture with an asymmetric binding of PGC-1 alpha to homodimeric ERR. Conclusions/Significance: These studies provide the molecular determinants for the specificity of interactions between PGC-1 alpha and the ERRs, whereby negative cooperativity prevails in the binding of the coactivators to these receptors. Our work indicates that allosteric regulation may be a general mechanism controlling the binding of the coactivators to homodimers.