Abstract
A subset of nuclear receptors (NRs) function as obligate heterodimers with retinoid X receptor (RXR), allowing integration of ligand-dependent signals across the dimer interface via an unknown structural mechanism. Using nuclear magnetic resonance (NMR) spectroscopy, x-ray crystallography and hydrogen/deuterium exchange (HDX) mass spectrometry, here we show an allosteric mechanism through which RXR co-operates with a permissive dimer partner, peroxisome proliferator-activated receptor (PPAR)-γ, while rendered generally unresponsive by a non-permissive dimer partner, thyroid hormone (TR) receptor. Amino acid residues that mediate this allosteric mechanism comprise an evolutionarily conserved network discovered by statistical coupling analysis (SCA). This SCA network acts as a signalling rheostat to integrate signals between dimer partners, ligands and coregulator-binding sites, thereby affecting signal transmission in RXR heterodimers. These findings define rules guiding how NRs integrate two ligand-dependent signalling pathways into RXR heterodimer-specific responses.
Highlights
A subset of nuclear receptors (NRs) function as obligate heterodimers with retinoid X receptor (RXR), allowing integration of ligand-dependent signals across the dimer interface via an unknown structural mechanism
A crystal structure of the thyroid hormone (TR)/RXR heterodimer defines a structural mechanism for this silencing, which occurs through a sequence of conformational relays between the helix 11 pairs that constitute most of the dimer interface, transferred to a rotation of helix 5 in the core of the RXR ligand-binding and transactivation domain (LBD), leading to disruption of the adjacent co-regulator- and ligand-binding sites
Agonist binding quenches the ms–ms conformational dynamics of the apoRXRa ligand-binding pocket and surrounding regions, including the Activation Function-2 (AF-2) surface. This mechanism is supported by hydrogen/deuterium exchange (HDX) mass spectrometry studies, which demonstrate stabilization of the RXRa ligand-binding pocket and AF-2 surface on ligand binding[40,41,42]
Summary
A subset of nuclear receptors (NRs) function as obligate heterodimers with retinoid X receptor (RXR), allowing integration of ligand-dependent signals across the dimer interface via an unknown structural mechanism. We have defined a structural mechanism whereby graded agonists and non-agonists do not fully stabilize the conformational dynamics of the AF-2 surface[4,25,26,27] It is poorly understood how ligand binding to one LBD controls co-regulator recruitment to its dimer partner within a NR heterodimer complex. A crystal structure of the TR/RXR heterodimer defines a structural mechanism for this silencing, which occurs through a sequence of conformational relays between the helix 11 pairs that constitute most of the dimer interface, transferred to a rotation of helix 5 in the core of the RXR LBD, leading to disruption of the adjacent co-regulator- and ligand-binding sites This allosteric signalling pathway is further confirmed by NMR and hydrogen/deuterium exchange (HDX) mass spectrometry. Analysis of other NR dimers reveals that these structural changes are part of an evolutionarily conserved energetic network, defined by a statistical coupling analysis (SCA) method[10], where helix 5 functions more generally as a signalling rheostat that integrates signals with the dimer interface, ligand and coregulator-binding sites
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