Structural Insight into the Constitutive Repression Function of the Nuclear Receptor Rev-erbβ

Woo, Eui-Jeon; Jeong, Dae Gwin; Lim, Mi Youn; Kim, Seung Jun; Kim, Kyung Jin; Yoon, Sei Mee; Park, Byoung Chul; Ryu, Seong Eon

doi:10.1016/j.jmb.2007.08.037

Cited by 49 publications

(66 citation statements)

References 53 publications

(67 reference statements)

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“…FLRev-erb␤ purifies as a homodimer, in accord with studies of the LBD (apoRev-erb␤ and the Rev-erb␣ LBD⅐ID1 complex) (27,29) and DBD (Rev-erb␣ DBD bound to the Rev-DR2 promoter element) (80,81). FLRev-erb␤ binds with high affinity (K 0.5 values Ͻ100 nM) and cooperatively to DNA Rev-REs, yielding Hill coefficients between 1.6 and 2.0 for interactions with the TR/FAM-Rev-DR2 and FAM-Bmal1 promoter.…”

Section: Discussionmentioning

confidence: 88%

“…Rev-erb␣ and Rev-erb␤ isoforms are unique to the NR superfamily in that they lack ␣-helix 12, rendering them unable to associate with a coactivator. Thus, these NRs are thought to function exclusively as repressors through binding of NCoR1, although Rev-erb␤ has been shown to activate Srebp-1c in skeletal muscle (29,30).…”

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confidence: 99%

“…For example, titration of purified Rev-erb␣/␤ LBDs with Fe 3ϩ -and Fe 2ϩ -heme decreases the affinity of Rev-erb for small peptides encompassing the NCoR1 interaction domains (16,34,36). In addition, when the crystal structures of apoRev-erb␤ LBD (29), Fe 3ϩ -heme-bound Rev-erb␤ LBD (36), and Rev-erb␣ LBD in complex with the NCoR1 interaction domain 1 (ID1) peptide (27) are compared, it is apparent that heme binding induces structural rearrangements that would cause significant steric clash between ␣-helix 3 of the LBD and a unique anti-parallel ␤-sheet of ID1. Furthermore, Trp402 and the heme axial ligand His-568 (Rev-erb␤ amino acid numbering), which provide hydrophobic interactions in the heme-binding pocket, is unfavorably positioned to accommodate heme in the ID1⅐Rev-erb␣ structure.…”

mentioning

confidence: 99%

“…Furthermore, Trp402 and the heme axial ligand His-568 (Rev-erb␤ amino acid numbering), which provide hydrophobic interactions in the heme-binding pocket, is unfavorably positioned to accommodate heme in the ID1⅐Rev-erb␣ structure. In sum, although studies with full-length proteins in cells provided a model in which heme has a robust stimulatory effect on the interaction between Rev-erb␣ and NCoR1 (16), biochemical and structural studies (16,27,29,34,36) indicate that heme binding may destabilize the Rev-erb␣/␤⅐NCoR1 complex. However, it should be re-emphasized that these in vitro studies were performed with the isolated LBD and NCoR1 peptides.…”

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confidence: 99%

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High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor

Carter

Gupta

Ragsdale

2016

Journal of Biological Chemistry

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Rev-erb␣ and Rev-erb␤ are heme-binding nuclear receptors (NR) that repress the transcription of genes involved in regulating metabolism, inflammation, and the circadian clock. Previous gene expression and co-immunoprecipitation studies led to a model in which heme binding to Rev-erb␣ recruits nuclear receptor corepressor 1 (NCoR1) into an active repressor complex. However, in contradiction, biochemical and crystallographic studies have shown that heme decreases the affinity of the ligand-binding domain of Rev-erb NRs for NCoR1 peptides. One explanation for this discrepancy is that the ligand-binding domain and NCoR1 peptides used for in vitro studies cannot replicate the key features of the full-length proteins used in cellular studies. However, the combined in vitro and cellular results described here demonstrate that heme does not directly promote interactions between full-length Rev-erb␤ (FLRev-erb␤) and an NCoR1 construct encompassing all three NR interaction domains. NCoR1 tightly binds both apo-and heme-replete FLRev-erb␤⅐DNA complexes; furthermore, heme, at high concentrations, destabilizes the FLRev-erb␤⅐NCoR1 complex. The interaction between FLRev-erb␤ and NCoR1 as well as Reverb␤ repression at the Bmal1 promoter appear to be modulated by another cellular factor(s), at least one of which is related to the ubiquitin-proteasome pathway. Our studies suggest that heme is involved in regulating the degradation of Rev-erb␤ in a manner consistent with its role in circadian rhythm maintenance. Finally, the very slow rate constant (10 ؊6 s ؊1 ) of heme dissociation from Rev-erb␤ rules out a prior proposal that Reverb␤ acts as an intracellular heme sensor.Nuclear receptors (NRs) 2 are eukaryotic transcription factors that activate or repress gene expression in response to binding small signaling molecules such as steroid hormones, lipophilic vitamins, and fatty acids (1). Genes regulated by NRs are involved in a myriad of cellular processes ranging from metabolic homeostasis to growth and development. The subjects of this article, Rev-erb␣ and Rev-erb␤, are NRs that have overlapping functions and tissue expression patterns (2-9) and are under circadian control (10 -12). Rev-erb NRs repress the transcription of key genes, e.g. Bmal1, CLOCK, and Rev-erb␣ itself, involved in regulating the molecular clock (13)(14)(15). This is accomplished in part through the formation of a heterodimeric Bmal1-CLOCK complex that activates the transcription of clock-controlled genes including Rev-erb␣/␤, completing a critical feedback loop required for circadian rhythm maintenance (6, 7). Rev-erb␣ and Rev-erb␤ also regulate the expression of genes involved in gluconeogenesis, lipid homeostasis, and immune responses, ultimately synchronizing these processes to the diurnal cycle (16 -21).The multiple functions of NRs (DNA, ligand, and coregulator binding) are accomplished through their modular structure (22, 23). The N-terminal A/B domain is hypervariable, is involved in ligand-independent transcriptional regulation, and is subject to ...

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Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor

Carter

Gupta

Ragsdale

2016

Journal of Biological Chemistry

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“…A prime candidate is Rev-erbb (NR1D2), whose DNAbinding domain (DBD) in mice is ;96% identical to that of Rev-erba (CLUSTAL W) (Retnakaran et al 1994) and has been shown to bind the canonical Rev-erba-binding site (Dumas et al 1994;Woo et al 2007;Pardee et al 2009). Interestingly, among the NRs, only the estrogen receptors (ERs) display the same degree of DBD conservation among the two subtypes (CLUSTAL W).…”

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confidence: 99%

Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function

Bugge¹,

Feng²,

Everett³

et al. 2012

Genes Dev.

439

420

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The nuclear receptor Rev-erba regulates circadian rhythm and metabolism, but its effects are modest and it has been considered to be a secondary regulator of the cell-autonomous clock. Here we report that depletion of Reverba together with closely related Rev-erbb has dramatic effects on the cell-autonomous clock as well as hepatic lipid metabolism. Mouse embryonic fibroblasts were rendered arrhythmic by depletion of both Rev-erbs. In mouse livers, Rev-erbb mRNA and protein levels oscillate with a diurnal pattern similar to that of Rev-erba, and both Rev-erbs are recruited to a remarkably similar set of binding sites across the genome, enriched near metabolic genes. Depletion of both Rev-erbs in liver synergistically derepresses several metabolic genes as well as genes that control the positive limb of the molecular clock. Moreover, deficiency of both Rev-erbs causes marked hepatic steatosis, in contrast to relatively subtle changes upon loss of either subtype alone. These findings establish the two Rev-erbs as major regulators of both clock function and metabolism, displaying a level of subtype collaboration that is unusual among nuclear receptors but common among core clock proteins, protecting the organism from major perturbations in circadian and metabolic physiology.

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Role of CO in Circadian Clock

Kitagishi

Sagami

2022

Carbon Monoxide in Drug Discovery

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Structural Insight into the Constitutive Repression Function of the Nuclear Receptor Rev-erbβ

Cited by 49 publications

References 53 publications

High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor

High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor

Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function

Role of CO in Circadian Clock

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