Nuclear receptor interdomain communication is mediated by the hinge with ligand specificity
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Abstract
Nuclear receptors are ligand-induced transcription factors that bind directly to target genes and regulate their expression. Ligand binding initiates conformational changes that propagate to other domains, allosterically regulating their activity. The nature of this interdomain communication in nuclear receptors is poorly understood, largely owing to the difficulty of experimentally characterizing full-length structures. We have applied computational modeling approaches to describe and study the structure of the full length farnesoid X receptor (FXR), approximated by the DNA binding domain (DBD) and ligand binding domain (LBD) connected by the flexible hinge region. Using extended molecular dynamics simulations (> 10 microseconds) and enhanced sampling simulations, we provide evidence that ligands selectively induce domain rearrangement, leading to interdomain contact. We use protein-protein interaction assays to provide experimental evidence of these interactions, identifying a critical role of the hinge in mediating interdomain contact. Our results illuminate previously unknown aspects of interdomain communication in FXR and provide a framework to enable characterization of other full length nuclear receptors.
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These results suggest an important role for the hinge in mediating contact between LBD and DBD, as well as the ligand-specific nature of this interaction.
This is a really interesting study on the complex interplay between NHR domains! I was wondering if you tested interactions between these domains using in vitro protein-protein interaction assays that can sidestep possible complications of the heterologous cell-based Gal4 system (i.e. “pull-down” assays, etc.)?
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As nuclear receptors share a conserved structure and mechanism, we anticipate that similar ligand-modulated domain rearrangement will be observed in other receptors
Are there any naturally occurring mutations associated with diseases that map to regions that your model predicts would disrupt interdomain interactions? Or conversely, can you generate mutations that your model predicts would disrupt interactions and measure the effects on transcription use simple reporter assays and full-length constructs?
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