PPARγ phase separates with RXRα at PPREs to regulate target gene expression

Li, Zhean; Luo, Lingling; Yu, Wenxia; Li, Ping; Ou, Danfeng; Liu, Jia; Ma, Hanhui; Sun, Qiang; Liang, Aibin; Huang, Cheng; Tian, Chao; Huang, Xingxu

doi:10.1038/s41421-022-00388-0

Cited by 23 publications

(11 citation statements)

References 66 publications

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“…The LLPS paradigm provides a new framework to understand the mechanism underlying the physiological function of NRs. NRs that are known to undergo LLPS leading to the formation of MLOs or liquid droplets in vitro include AR [ 24 ], ER [ 26 ], GR [ 25 ], PPARγ [ 23 ] and RXRγ [ 27 , 28 ]. In different NRs, particular regions or domains with unique biochemical natures present different phase separation potentials.…”

Section: Discussionmentioning

confidence: 99%

“…The structured domains of androgen receptor (AR), PPARγ and glucocorticoid receptor (GR) are the main drivers of LLPS. In particular, the formation of AR and PPARγ liquid condensates is mediated by DBD [ 23 , 24 ], whereas GR is mediated by LBD [ 25 ]. On the other hand, for the estrogen receptor (ER) and RXRγ, AB regions seem to be essential for condensate formation [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

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Phase separation propensity of the intrinsically disordered AB region of human RXRβ

Sołtys

Ożyhar

2023

Cell Commun Signal

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RXRβ is one of three subtypes of human retinoid X receptor (RXR), a transcription factor that belongs to the nuclear receptor superfamily. Its expression can be detected in almost all tissues. In contrast to other subtypes – RXRα and RXRγ – RXRβ has the longest and unique N-terminal sequence called the AB region, which harbors a ligand-independent activation function. In contrast to the functional properties of this sequence, the molecular properties of the AB region of human RXRβ (AB_hRXRB) have not yet been characterized. Here, we present a systematic biochemical and biophysical analysis of recombinant AB_hRXRB, along with in silico examinations, which demonstrate that AB_hRXRB exhibits properties of a coil-like intrinsically disordered region. AB_hRXRB possesses a flexible structure that is able to adopt a more ordered conformation under the influence of different environmental factors. Interestingly, AB_hRXRB promotes the formation of liquid–liquid phase separation (LLPS), a phenomenon previously observed for the AB region of another human subtype of RXR – RXRγ (AB_hRXRG). Although both AB regions seem to be similar in terms of their ability to induce phase separation, they clearly differ in the sensitivity to factors driving and regulating LLPS. This distinct LLPS response to environmental factors driven by the unique amino acid compositions of AB_hRXRB and AB_hRXRG can be significant for the specific modulation of the transcriptional activation of target genes by different subtypes of RXR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phase separation propensity of the intrinsically disordered AB region of human RXRβ

Sołtys

Ożyhar

2023

Cell Commun Signal

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“…We found that although predominantly disordered, the AF-1 is characterized by transient long-range intramolecular contacts that can be enhanced by decreasing negative charge repulsion. Thus, a change in AF-1 structure and compaction could occur under cellular states that would affect protein net charge, such as the presence of binding partners including other proteins, nucleic acids (mRNA and chromatin), or small molecule metabolites 1 ; upon post-translational modification of PPARγ 42 ; or cellular compartments with localized changes in ionic strength or pH such as phase separated biomolecular condensates 43 .…”

Section: Discussionmentioning

confidence: 99%

Structural basis of interdomain communication in PPARγ

Mosure

Munoz-Tello²,

Kuo

et al. 2022

Preprint

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PPARγ is a nuclear receptor transcription factor that regulates adipogenic and insulin sensitizing gene programs via two activation function (AF) regulatory domains: a ligand-dependent AF-2 coregulator interaction surface within the C-terminal ligand-binding domain (LBD) and an N-terminal disordered AF-1 domain (NTD or A/B region). Here, we show the AF-1 contains an evolutionary conserved Trp-Pro motif that populates two long-lived AF-1 conformations via proline cis/trans isomerization. The Trp-Pro motif participates in transient intradomain AF-1 contacts and interdomain contacts with two surfaces of the LBD (β-sheet and AF-2). Mutagenesis indicates the Pro residue negatively regulates PPARγ transcriptional output, suggesting a potential regulatory mechanism for AF-1 isomerization. Our findings provide a structural rationale to explain previous in vitro and cellular studies that reported interdomain functional communication between the PPARγ AF-1 and LBD. Our study also illuminates a structural biology platform to study how disordered domains in nuclear receptors influence their structure and function.

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“…These proteins heterodimerize with retinoid X receptor (RXR) and bind to a corepression complex of certain proteins. The heterodimers bind to a part of a gene area known as "peroxisome proliferator response elements (PPREs)" through their DNA binding domain (DBD) 2,3 .…”

Section: Introductionmentioning

confidence: 99%

Peroxisome Proliferator- Activated Receptors (PPARs): A Review on Effects on Glucose Metabolism, Energy Homeostasis and Cardiovascular System

Al-Naemi¹

2022

Ann Coll Med Mosul

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Background: Molecular biology and human medical genetics have introduced several novel biomarkers giving control over vital body functions, of these are transcriptional factors known as peroxisome proliferator activated-receptors "PPARs". The aim of this review is to shed light on available online information and published research works about these biomarkers. The current review will try to display those findings mainly related to energy homeostasis, glucose metabolism, insulin sensitivity and some cardiovascular interactions. Methods: a literature review about peroxisome proliferator activated-receptors and their roles in controlling some vital body functions has been made and recorded. Search covered published investigations and research works over the last three decades as accessible. Results: peroxisome proliferator activated-receptors have crucial roles in controlling a big deal of vital biological processes in humans. Conclusions: Peroxisome proliferator-activated receptors are important transcriptional factors with clinical impacts. Literature shows a wide spectrum of effects and interactions through affecting many genes involved in processes of glucose homeostasis, energy balance, and peripheral insulin sensitization in addition to interfering with processes of inflammation, angiogenesis, blood pressure control and atherosclerosis.

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PPARγ phase separates with RXRα at PPREs to regulate target gene expression

Cited by 23 publications

References 66 publications

Phase separation propensity of the intrinsically disordered AB region of human RXRβ

Phase separation propensity of the intrinsically disordered AB region of human RXRβ

Structural basis of interdomain communication in PPARγ

Peroxisome Proliferator- Activated Receptors (PPARs): A Review on Effects on Glucose Metabolism, Energy Homeostasis and Cardiovascular System

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