The nuclear receptor signalling scaffold: insights from full-length structures

Abstract

EMBO J 31 2, 291–300 (2012); published online December 16 2011

Nuclear receptors (NRs) can be conceptualized as highly dynamic scaffold proteins, where binding of ligand, DNA or transcriptional coregulator proteins can allosterically change the scaffold structure and direct changes in subsequent binding events. In this issue of The EMBO Journal, Orlov et al present the first cryo-EM structure of a NR complex, a technically challenging feat for the 100-kDa complex of the heterodimer of the vitamin D receptor (VDR), Retinoid X receptor (RXR) and their cognate DNA response element. VDR is one of the few NRs for which the hinge between the ligand-binding domain (LBD) and DNA-binding domain is an extended helix, which enforced a bend in VDR/RXR to an L-shaped architecture. The hinge domain is thus a key regulator of the relative orientation of the LBDs to the DNA, which will impact how transcriptional coregulator complexes are oriented towards the chromatin. It further suggests that the positioning of the hinge may serve as a conduit of structural information, determining how specific DNA sequences can modulate activity in the LBDs.

Figure 1

(A) Architecture of full-length NRs. VDR has an extended helix in the hinge domain that positions the LBD, and may limit inter-domain flexibility. (B) A model for regulation of the LBD by DNA binding. Changes in the positioning of the hinge could modulate the LBD dimer interface, and in turn change the conformation of helix 12, which forms part of the coactivator binding site. (C) For the steroid receptors AR, GR, MR and PR, interaction with DNA (or other proteins) could stabilize different low affinity dimer interfaces in the LBD.