Fiche publication


Date publication

janvier 2013

Auteurs

Membres identifiés du Cancéropôle Est :
Dr DEJAEGERE Annick , Dr MORAS Dino , Dr BILLAS Isabelle


Tous les auteurs :
Takacs M, Petoukhov MV, Atkinson RA, Roblin P, Ogi FX, Demeler B, Potier N, Chebaro Y, Dejaegere A, Svergun DI, Moras D, Billas IM

Résumé

BACKGROUND: PGC-1alpha is a crucial regulator of cellular metabolism and energy homeostasis that functionally acts together with the estrogen-related receptors (ERRalpha and ERRgamma) in the regulation of mitochondrial and metabolic gene networks. Dimerization of the ERRs is a pre-requisite for interactions with PGC-1alpha and other coactivators, eventually leading to transactivation. It was suggested recently (Devarakonda et al) that PGC-1alpha binds in a strikingly different manner to ERRgamma ligand-binding domains (LBDs) compared to its mode of binding to ERRalpha and other nuclear receptors (NRs), where it interacts directly with the two ERRgamma homodimer subunits. METHODS/PRINCIPAL FINDINGS: Here, we show that PGC-1alpha receptor interacting domain (RID) binds in an almost identical manner to ERRalpha and ERRgamma homodimers. Microscale thermophoresis demonstrated that the interactions between PGC-1alpha 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-1alpha RID that interacts with ERRs. Consistent with these findings, the solution structures of PGC-1alpha/ERRalpha LBDs and PGC-1alpha/ERRgamma LBDs complexes share an identical architecture with an asymmetric binding of PGC-1alpha to homodimeric ERR. CONCLUSIONS/SIGNIFICANCE: These studies provide the molecular determinants for the specificity of interactions between PGC-1alpha 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.

Référence

PLoS One. 2013 Jul 9;8(7):e67810