The asymmetric binding of PGC-1? to the ERR? and ERR? nuclear receptor homodimers involves a similar recognition mechanism.

ABSTRACT:

Background

PGC-1? is a crucial regulator of cellular metabolism and energy homeostasis that functionally acts together with the estrogen-related receptors (ERR? and ERR?) in the regulation of mitochondrial and metabolic gene networks. Dimerization of the ERRs is a pre-requisite for interactions with PGC-1? and other coactivators, eventually leading to transactivation. It was suggested recently (Devarakonda et al) that PGC-1? binds in a strikingly different manner to ERR? ligand-binding domains (LBDs) compared to its mode of binding to ERR? and other nuclear receptors (NRs), where it interacts directly with the two ERR? homodimer subunits.

Methods/principal findings

Here, we show that PGC-1? receptor interacting domain (RID) binds in an almost identical manner to ERR? and ERR? homodimers. Microscale thermophoresis demonstrated that the interactions between PGC-1? 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? RID that interacts with ERRs. Consistent with these findings, the solution structures of PGC-1?/ERR? LBDs and PGC-1?/ERR? LBDs complexes share an identical architecture with an asymmetric binding of PGC-1? to homodimeric ERR.

Conclusions/significance

These studies provide the molecular determinants for the specificity of interactions between PGC-1? 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.

SUBMITTER: Takacs M 

PROVIDER: S-EPMC3706463 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature