Communication between the ERRα Homodimer Interface and the PGC-1α Binding Surface via the Helix 8–9 Loop

Greschik, Holger; Althage, Magnus; Flaig, Ralf; Sato, Yoshihiko; Chavant, Virginie; Peluso‐Iltis, Carole; Choulier, Laurence; Cronet, Philippe; Rochel, Natacha; Schüle, Roland; Strömstedt, Per-Erik; Moras, Dino

doi:10.1074/jbc.m801920200

Cited by 35 publications

(38 citation statements)

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“…In addition, the crystal structure of ERRα bound to a PGC-1α fragment exhibits a similar asymmetry in the coactivator peptide binding mode and confirms the general character of the model (20). The structural explanation of the negative cooperativity is that the conformational changes in the second monomer affect the binding surface and thus the affinity for the same CoA domain.…”

Section: Discussionmentioning

confidence: 48%

“…Our results suggest that the N-terminal flanking residues of the LXXLL motif that join the dimer interface are the most effective in the control mechanism. An allosteric communication involving the N-terminal end of PGC-1α peptide and ERRα homodimer via the loop 8-9 has been characterized (20). The functional implications of asymmetry were illustrated in the case of the RXR-RAR heterodimer bound to the response element of RARβ2 gene promoter (14).…”

Section: Discussionmentioning

confidence: 99%

“…Packing analysis (Fig. 1) shows that crystals are built from dimeric entities similar to those observed in the crystal structures of ER (19), ERR (20), PPAR (21), or LXR (22)(23). Both subunits adopt the active conformation, with the C-terminal activation helix H12 capping the ligand-binding pocket and the SRC-1 NR2 peptide bound to the surface formed by residues from helices H3, H4, and H12 ( Fig.…”

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confidence: 99%

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Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

Ősz

Brélivet

Peluso‐Iltis

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Transcription regulation by steroid hormones, vitamin derivatives, and metabolites is mediated by nuclear receptors (NRs), which play an important role in ligand-dependent gene expression and human health. NRs function as homodimers or heterodimers and are involved in a combinatorial, coordinated and sequentially orchestrated exchange between coregulators (corepressors, coactivators). The architecture of DNA-bound functional dimers positions the coregulators proteins. We previously demonstrated that retinoic acid (RAR-RXR) and vitamin D3 receptors (VDR-RXR) heterodimers recruit only one coactivator molecule asymmetrically without steric hindrance for the binding of a second cofactor. We now address the problem of homodimers for which the presence of two identical targets enhances the functional importance of the mode of binding. Using structural and biophysical methods and RAR as a model, we could dissect the molecular mechanism of coactivator recruitment to homodimers. Our study reveals an allosteric mechanism whereby binding of a coactivator promotes formation of nonsymmetrical RAR homodimers with a 2∶1 stoichiometry. Ligand conformation and the cofactor binding site of the unbound receptor are affected through the dimer interface. A similar control mechanism is observed with estrogen receptor (ER) thus validating the negative cooperativity model for an established functional homodimer. Correlation with published data on other NRs confirms the general character of this regulatory pathway.allostery | structure T he superfamily of nuclear receptors (NRs) comprises liganddependent transcription factors involved in the regulation of gene expression. They constitute key drug targets for human diseases such as cancer, osteoporosis, obesity, or type II diabetes (1-2). NRs share a common structural organization with a variable amino-terminal domain, a conserved DNA-binding domain (DBD), and a C-terminal ligand-binding domain (LBD) linked by a flexible hinge peptide. In addition to the ligand-binding pocket, the LBD comprises dimerization surfaces and the sites for coregulator interactions. In the classic mode of action, in absence of ligand, some NRs are associated with corepressors (NCoRs) that harbor histone-deacetylase activity to maintain the chromatin in a transcriptionally silent state (3-4). Upon ligand binding, DNA-bound receptors recruit coactivators like the steroid receptor coactivator 1 (SRC-1), a member of p160 CoA family (5), to enhance target gene expression. The receptor interaction domain (RID) of the coactivators is responsible for the interaction with NRs and contains several copies of the short consensus interaction motif LXXLL (6).The vast majority of NRs functions as dimers. RAR, like the vitamin D (VDR) and thyroid hormone (TR) receptors, heterodimerizes with rexinoid receptors (RXRs) (7). Their ability to form homodimers is also documented (8-10). RAR homodimers have been shown to be functional in yeast using a two-hybrid system, and their activity is further enhanced by the presence of SRC-2 c...

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Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

Ősz

Brélivet

Peluso‐Iltis

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…1 A and B) located within the activation domain of PGC-1α and the nuclear receptor ligand binding domain (LBD). The broad range of physiologic processes mediated by PGC-1α and the large repertoire of nuclear receptors with which it partners necessitate a deeper understanding of how the coactivator achieves specificity despite the similarity in its interactions with members of the superfamily (10)(11)(12)(13)(14)(15)(16). Structural analyses of these interactions have been restricted to the use of small peptides representative of single LXXLL motifs.…”

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confidence: 99%

Disorder-to-order transition underlies the structural basis for the assembly of a transcriptionally active PGC-1α/ERRγ complex

Devarakonda

Gupta

Chalmers

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Peroxisome proliferator activated receptor (PPAR) γ coactivator-1α (PGC-1α) is a potent transcriptional coactivator of oxidative metabolism and is induced in response to a variety of environmental cues. It regulates a broad array of target genes by coactivating a whole host of transcription factors. The estrogen-related receptor (ERR) family of nuclear receptors are key PGC-1α partners in the regulation of mitochondrial and tissue-specific oxidative metabolic pathways; these receptors also demonstrate strong physical and functional interactions with this coactivator. Here we perform comprehensive biochemical, biophysical, and structural analyses of the complex formed between PGC-1α and ERRγ. PGC-1α activation domain (PGC-1 α 2–220 ) is intrinsically disordered with limited secondary and no defined tertiary structure. Complex formation with ERRγ induces significant changes in the conformational mobility of both partners, highlighted by significant stabilization of the ligand binding domain (ERRγLBD) as determined by HDX (hydrogen/deuterium exchange) and an observed disorder-to-order transition in PGC-1 α 2–220 . Small-angle X-ray scattering studies allow for modeling of the solution structure of the activation domain in the absence and presence of ERRγLBD, revealing a stable and compact binary complex. These data show that PGC-1 α 2–220 undergoes a large-scale conformational change when binding to the ERRγLBD, leading to substantial compaction of the activation domain. This change results in stable positioning of the N-terminal part of the activation domain of PGC-1α, favorable for assembly of an active transcriptional complex. These data also provide structural insight into the versatile coactivation profile of PGC-1α and can readily be extended to understand other transcriptional coregulators.

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“…contains the canonical LXXLL motif (NR box2), whereas the LBD of ERRa also binds efficiently an untypical, LXXYL-containing region (NR box3) (Greschik et al, 2008).…”

Section: Transcription Regulation By Nuclear Hormone Receptorsmentioning

confidence: 99%

Structural insights into transcription complexes

Berger

Blanco

Boelens

et al. 2011

Journal of Structural Biology

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a b s t r a c tControl of transcription allows the regulation of cell activity in response to external stimuli and research in the field has greatly benefited from efforts in structural biology. In this review, based on specific examples from the European SPINE2-COMPLEXES initiative, we illustrate the impact of structural proteomics on our understanding of the molecular basis of gene expression. While most atomic structures were obtained by X-ray crystallography, the impact of solution NMR and cryo-electron microscopy is far from being negligible. Here, we summarize some highlights and illustrate the importance of specific technologies on the structural biology of protein-protein or protein/DNA transcription complexes: structure/ function analysis of components the eukaryotic basal and activated transcription machinery with focus on the TFIID and TFIIH multi-subunit complexes as well as transcription regulators such as members of the nuclear hormone receptor families. We also discuss molecular aspects of promoter recognition and epigenetic control of gene expression.

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Communication between the ERRα Homodimer Interface and the PGC-1α Binding Surface via the Helix 8–9 Loop

Cited by 35 publications

References 50 publications

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

Disorder-to-order transition underlies the structural basis for the assembly of a transcriptionally active PGC-1α/ERRγ complex

Structural insights into transcription complexes

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