The asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue PLoS ONE Année : 2013

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

Résumé

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.
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hal-02651428 , version 1 (29-05-2020)

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Maria Takacs, Maxim V. Petoukhov, R. Andrew Atkinson, Pierre Roblin, François-Xavier Ogi, et al.. The asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism. PLoS ONE, 2013, 8 (7), ⟨10.1371/journal.pone.0067810⟩. ⟨hal-02651428⟩
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