title: The asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Integrative Structural Biology, Institute of Genetics and Molecular and Cellular Biology (IGBMC), Centre National de la Recherche Scientifique (CNRS), UMR 7104, Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Université de Strasbourg (UdS), Illkirch, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Takacs
authors.forename: Maxim V
authors.initials: MV
authors.lastname: Petoukhov
authors.forename: R Andrew
authors.initials: RA
authors.lastname: Atkinson
authors.forename: Pierre
authors.initials: P
authors.lastname: Roblin
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Ogi
authors.forename: Borries
authors.initials: B
authors.lastname: Demeler
authors.forename: Noelle
authors.initials: N
authors.lastname: Potier
authors.forename: Yassmine
authors.initials: Y
authors.lastname: Chebaro
authors.forename: Annick
authors.initials: A
authors.lastname: Dejaegere
authors.forename: Dmitri I
authors.initials: DI
authors.lastname: Svergun
authors.forename: Dino
authors.initials: D
authors.lastname: Moras
authors.forename: Isabelle M L
authors.initials: IM
authors.lastname: Billas
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D011960:Receptors, Estrogen / Q000737:chemistry / Q000378:metabolism*; D053838:Scattering, Small Angle; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014961:X-Ray Diffraction; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D021122:Protein Subunits; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C490917:ESRRG protein, human; C486497:PPARGC1A protein, human