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

TY - JOUR

T1 - The asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism

AU - Takacs, Maria

AU - Petoukhov, Maxim V

AU - Atkinson, R Andrew

AU - Roblin, Pierre

AU - Ogi, François-Xavier

AU - Demeler, Borries

AU - Potier, Noelle

AU - Chebaro, Yassmine

AU - Dejaegere, Annick

AU - Svergun, Dmitri I

AU - Moras, Dino

AU - Billas, Isabelle M L

PY - 2013/7/9

Y1 - 2013/7/9

N2 - 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.

AB - 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.

KW - SMALL-ANGLE SCATTERING

KW - HORMONE RESPONSE ELEMENT

KW - TRANSCRIPTIONAL COACTIVATOR

KW - BIOLOGICAL MACROMOLECULES

KW - CRYSTAL-STRUCTURE

KW - STRUCTURAL BASIS

KW - LIGAND-BINDING

KW - PGC-1

KW - EXPRESSION

KW - DISEASE

U2 - 10.1371/journal.pone.0067810

DO - 10.1371/journal.pone.0067810

M3 - Article

C2 - 23874451

SN - 1932-6203

VL - 8

JO - PLoS ONE

JF - PLoS ONE

IS - 7

M1 - e67810

ER -