Abstract
Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations. Here we report the quaternary architecture of multi-domain retinoic acid receptor β–retinoic X receptor α (RARβ–RXRα) heterodimer bound to DNA, ligands and coactivator peptides, examined through crystallographic, hydrogen–deuterium exchange mass spectrometry, mutagenesis and functional studies. The RARβ ligand-binding domain (LBD) and DNA-binding domain (DBD) are physically connected to foster allosteric signal transmission between them. Direct comparisons among all the multi-domain NRs studied crystallographically to date show significant variations within their quaternary architectures, rather than a common architecture adhering to strict rules. RXR remains flexible and adaptive by maintaining loosely organized domains, while its heterodimerization partners use a surface patch on their LBDs to form domain-domain interactions with DBDs.
Highlights
Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations
Employing full-length or multi-domain NR complexes bound to DNA, crystal structures have been reported to date only for the peroxisome proliferator-activated receptor γ–retinoic X receptor α (PPARγ–RXRα) heterodimer (PDB codes: 3DZY, 3DZU, and 3E00)[4], the hepatocyte nuclear factor 4α (HNF-4α) homodimer (PDB code: 4IQR)[5], and the liver X receptor β (LXRβ)–RXRα heterodimer (PDB code: 4NQA)[6]
We sought here to understand the quaternary architecture of RARβ–RXRα heterodimer in the wider context of other recently reported crystal structures of multi-domain NR complexes, to assess their level of overall variations and to pinpoint specific sites where domain–domain junctions are formed in each case
Summary
Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations. RXR remains flexible and adaptive by maintaining loosely organized domains, while its heterodimerization partners use a surface patch on their LBDs to form domain-domain interactions with DBDs. Nuclear receptors (NRs) are a family of transcription factors that respond to lipophilic ligands and control a variety of metazoan gene programs[1, 2]. To directly visualize how different domains of RAR and RXR polypeptides physically interact within and between their polypeptides, we conducted crystallographic studies using multi-domain recombinant RARβ and RXRα proteins Both receptors’ ligands, including REA for RARβ and 9CR for RXRα, their idealized DNA response element (RARE) and coactivator peptides were included to visualize how all these components are configured and interact within the overall complex. We sought here to understand the quaternary architecture of RARβ–RXRα heterodimer in the wider context of other recently reported crystal structures of multi-domain NR complexes, to assess their level of overall variations and to pinpoint specific sites where domain–domain junctions are formed in each case
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