Biology subjects

Mosure, S. A.

Publications and source records attributed to Mosure, S. A..

4 recordsLinked to original sources

bioRxiv2026

Negative regulation of TH17-mediated inflammation by the nuclear receptor REV-ERBβ

TH17 cells play a central role in several human autoimmune diseases. We and others reported the nuclear receptor, REV-ERB, as a cell-intrinsic repressor of TH17-mediated pathogenicity. REV-ERB{beta}, REV-ERBs closely related family member, is thought to be functionally redundant to REV-ERB, which we sought to explore in TH17-mediated immunity. Our data indicate that deletion of REV-ERB{beta} enhances TH17-mediated pro-inflammatory cytokine expression and exacerbated disease in mouse models of multiple sclerosis and colitis. RNA-sequencing indicates REV-ERB{beta} and REV-ERB do not have similar transcriptional profiles. REV-ERB{beta} does not appear to regulate gene expression through interaction with the classic co-repressor NCoR1, which is in contrast to REV-ERB in TH17 cells, nor does it utilize heme, its known endogenous ligand for its repressive functions. Our results establish that while REV-ERB{beta} also acts as a negative regulator of TH17-cell function and pathogenicity, it does so in a manner that is non-redundant, independent, and unique to REV-ERB.

immunology↗

bioRxiv2022

Structural basis of interdomain communication in PPARγ

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR{gamma}) regulates transcription 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) that functions through poorly understood structural mechanisms. Here, we show the PPAR{gamma} AF-1 contains an evolutionary conserved Trp-Pro motif that undergoes cis/trans isomerization, populating two long-lived conformations that participate in intradomain AF-1 and interdomain interactions including two surfaces in the C-terminal LBD ({beta}-sheet and the AF-2 surface), which are predicted in AlphaFold 3 models but not AlphaFold 2. NMR and chemical crosslinking mass spectrometry show that interdomain interactions occur for soluble isolated AF-1 and LBD proteins, as well as in full-length PPAR{gamma} in a phase separated state. Mutation of the region containing the Trp-Pro motif, which abrogates cis/trans isomerization of this region, impacts LBD interaction and reduces basal PPAR{gamma}-mediated transcription and agonist-dependent activation of PPAR{gamma}. Our findings provide structural insight into published in vitro and cellular studies that reported interdomain functional communication between the PPAR{gamma} AF-1 and LBD suggesting some of these effects may be mediated via AF-1/LBD interactions.

biochemistry↗

bioRxiv2020

Structural basis for heme-dependent NCoR binding to the transcriptional repressor REV-ERBβ

Heme is the endogenous ligand for the constitutively repressive REV-ERB nuclear receptors, REV-ERB (NR1D1) and REV-ERB{beta} (NR1D2), but how heme regulates REV-ERB activity remains unclear. While cellular studies indicate heme is required for the REV-ERBs to bind the corepressor NCoR and repress transcription, fluorescence-based biochemical assays and crystal structures suggest that heme displaces NCoR. Here, we show that heme artifactually influences detection of NCoR interaction in fluorescence-based assays. However, using fluorescence-independent methods, isothermal titration calorimetry and NMR spectroscopy, we demonstrate that heme directly increases REV-ERB{beta} ligand-binding domain (LBD) binding affinity for NCoR. We further report two crystal structures of REV-ERB{beta} LBD cobound to heme and NCoR peptides, which reveal the structural basis for heme-dependent NCoR binding to REV-ERB{beta}. By resolving previous contradictory biochemical, structural, and cellular studies, our findings should facilitate renewed progress toward understanding heme-dependent REV-ERB activity.

molecular biology↗

bioRxiv2018

Coincident binding of synthetic and natural ligands to the nuclear receptor PPARγ

Crystal structures of peroxisome proliferator-activated receptor gamma (PPAR{gamma}) have revealed overlapping binding modes for synthetic and natural/endogenous ligands, indicating competition for the orthosteric pocket. Here we show that cobinding of a synthetic ligand to the orthosteric pocket can push natural and endogenous PPAR{gamma} ligands (fatty acids) out of the orthosteric pocket towards an alternate ligand-binding site near the functionally important omega ({Omega}) loop. X-ray crystallography, NMR spectroscopy, all-atom molecular dynamics simulations, and mutagenesis coupled to quantitative functional assays reveal that synthetic ligand and fatty acid cobinding can form a \"ligand link\" to the {Omega} loop and synergistically affect the structure and function of PPAR{gamma}. These findings contribute to a growing body of evidence indicating ligand binding to nuclear receptors can be more complex than the classical one-for-one orthosteric exchange of a natural or endogenous ligand with a synthetic ligand.

biochemistry↗