The asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism

 

Maria Takacs, Maxim V. Petoukhov, R. Andrew Atkinson, Pierre Roblin, François-Xavier Ogi, Borries Demeler, Noelle Potier, Yassmine Chebaro, Annick Dejaegere, Dmitri I. Svergun, Dino Moras, Isabelle M. L. Billas

PloS ONE
2013 vol: 8 issue: 7 pp: e67810 doi: 10.1371/journal.pone.0067810

Abstract

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

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

CONCLUSIONS/SIGNIFICANCE:
These studies provide the molecular determinants for the specificity of interactions between PGC-1α 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.

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Topics: Small-angle scattering, Crystal structure, Dimers (Chemical physics), Sequence motif analysis, Biophysics, Molecular dynamics, Allosteric regulation, Protein structure prediction, Monolith – MicroScale Thermophoresis, MST, Proteins, Publications

 

 

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