Active nuclear receptors exhibit highly correlated AF-2 domain motions.
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 A 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.
Teotico
Denise G
DG
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Frazier
Monica L
ML
Ding
Feng
F
Dokholyan
Nikolay V
NV
Temple
Brenda R S
BR
Redinbo
Matthew R
MR
D000595:Amino Acid Sequence / Q000502:physiology; D001665:Binding Sites / Q000502:physiology; D017124:Conserved Sequence / Q000502:physiology; D019281:Dimerization; D004735:Energy Transfer / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D009038:Motion; D009687:Nuclear Proteins / Q000378:metabolism; D000077297:Pregnane X Receptor; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism
D009687:Nuclear Proteins; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D047488:Retinoid X Receptors