The asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism.
<h4>Background</h4>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 f...
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oai:doaj.org-article:0645df87374045a1b9f15e0fba416ec92021-11-18T07:38:13ZThe asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism.1932-620310.1371/journal.pone.0067810https://doaj.org/article/0645df87374045a1b9f15e0fba416ec92013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23874451/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methods/principal findings</h4>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.<h4>Conclusions/significance</h4>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.Maria TakacsMaxim V PetoukhovR Andrew AtkinsonPierre RoblinFrançois-Xavier OgiBorries DemelerNoelle PotierYassmine ChebaroAnnick DejaegereDmitri I SvergunDino MorasIsabelle M L BillasPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 7, p e67810 (2013) |
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| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q 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 The asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism. |
| description |
<h4>Background</h4>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.<h4>Methods/principal findings</h4>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.<h4>Conclusions/significance</h4>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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Maria Takacs |
| title |
The asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism. |
| title_short |
The asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism. |
| title_full |
The asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism. |
| title_fullStr |
The asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism. |
| title_full_unstemmed |
The asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism. |
| title_sort |
asymmetric binding of pgc-1α to the errα and errγ nuclear receptor homodimers involves a similar recognition mechanism. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/0645df87374045a1b9f15e0fba416ec9 |
| work_keys_str_mv |
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