Interactions governing transcriptional activity of nuclear receptors

Abstract

The key players in transcriptional regulation are transcription factors (TFs), proteins that bind specific DNA sequences. Several mechanisms exist to turn TFs ‘on’ and ‘off’, including ligand binding which induces conformational changes within TFs, subsequently influencing multiple inter- and intramolecular interactions to drive transcriptional responses. Nuclear receptors are a specific family of ligand-regulated TFs whose activity relies on interactions with DNA, coregulator proteins and other receptors. These multidomain proteins also undergo interdomain interactions on multiple levels, further modulating transcriptional outputs. Cooperation between these distinct interactions is critical for appropriate transcription and remains an intense area of investigation. In this review, we report and summarize recent findings that continue to advance our mechanistic understanding of how interactions between nuclear receptors and diverse partners influence transcription.

Nuclear hormone receptor NHR-49 is an essential regulator of stress resilience and healthy aging in Caenorhabditis elegans

“…The LBD binds ligands, whose presence or absence can regulate NHR activity, with additional regulation via post-translational modifications in the LBD and elsewhere ( Berrabah et al, 2011 ). The LBD also serves as a binding site for transcriptional coregulators, including coactivators and corepressors, which influence NHR transcriptional output ( Mouchiroud et al, 2014 ; Khan and Okafor, 2022 ; Scholtes and Giguère, 2022 ). The DBD and LBD also play roles in dimerization, as NHRs can function as monomers, homodimers, and/or heterodimers.…”

Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states

“…These include graded transcriptional activity (e.g., partial vs. full agonism), transcriptional repression (inverse agonism), and whether agonists and inverse agonists select natively populated structural conformations (conformational selection) or induce non-native conformations. X-ray crystallography and cryo-electron microscopy have provided structural insights into DNA- and coregulator-bound NR transcriptional complexes, including LBDs bound to different pharmacological ligands 6,7 . However, these structural methods that capture static snapshots of functionally relevant NR complexes fail to explain features relevant to the dynamic functional LBD conformational ensemble, which are detectable by other methods such as NMR spectroscopy 8 .…”