Abstract
Nuclear receptor ligand binding domains (LBDs) convert ligand binding events into changes in gene expression by recruiting transcriptional coregulators to a conserved activation function-2 (AF-2) surface. While most nuclear receptor LBDs form homo- or heterodimers, the human nuclear receptor pregnane X receptor (PXR) forms a unique and essential homodimer and is proposed to assemble into a functional heterotetramer with the retinoid X receptor (RXR). How the homodimer interface, which is located 30 Å from the AF-2, would affect function at this critical surface has remained unclear. By using 20- to 30-ns molecular dynamics simulations on PXR in various oligomerization states, we observed a remarkably high degree of correlated motion in the PXR–RXR heterotetramer, most notably in the four helices that create the AF-2 domain. The function of such correlation may be to create “active-capable” receptor complexes that are ready to bind to transcriptional coactivators. Indeed, we found in additional simulations that active-capable receptor complexes involving other orphan or steroid nuclear receptors also exhibit highly correlated AF-2 domain motions. We further propose a mechanism for the transmission of long-range motions through the nuclear receptor LBD to the AF-2 surface. Taken together, our findings indicate that long-range motions within the LBD scaffold are critical to nuclear receptor function by promoting a mobile AF-2 state ready to bind coactivators.
Highlights
The nuclear receptor (NR) superfamily of ligand-regulated transcription factors controls the expression of genes essential to metabolism, development and systemic homeostasis [1,2,3]
NR ligand binding domains (LBDs) contain a shallow activation function 2 (AF-2) surface formed by helices a3, a39, a4 and aAF that is essential for ligand-dependent interactions with transcriptional coregulators
It has been shown that this dimer interface is essential to pregnane X receptor (PXR) function, and that the specific disruption of homodimerization eliminates the ability of the receptor to interact with transcriptional coactivators like steroid receptor coactivator 1 (SRC-1), but does not impact PXR’s subcellular localization or its association with DNA, retinoid X receptor (RXR), or activating ligands [12]
Summary
The nuclear receptor (NR) superfamily of ligand-regulated transcription factors controls the expression of genes essential to metabolism, development and systemic homeostasis [1,2,3]. NR LBDs contain a shallow activation function 2 (AF-2) surface formed by helices a3, a39, a4 and aAF that is essential for ligand-dependent interactions with transcriptional coregulators. The PXR LBD, in contrast, contains a second oligomerization interface at the novel b-turn-b motif in which intercalating tryptophan and tyrosine residues (Trp-223/Tyr-225) lock across the dimer to form an aromatic zipper [4,5,12] (Figure 1A). It has been shown that this dimer interface is essential to PXR function, and that the specific disruption of homodimerization eliminates the ability of the receptor to interact with transcriptional coactivators like steroid receptor coactivator 1 (SRC-1), but does not impact PXR’s subcellular localization or its association with DNA, RXR, or activating ligands [12]. This work led to the proposal of a PXRRXR heterotetramer as the functional unit [12] (Figures 1A, 1B)
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