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

Abstract

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. Nuclear receptors (NRs) are a superfamily of transcription factors that regulate key aspects of development, metabolism and disease (Huang et al, 2010). NRs typically form transcriptionally active homodimers or heterodimers with another NR, that is, Retinoid X receptor (RXR). The classic modular domain organization of NRs includes a variable N-terminal domain (NTD) that may contain a ligand-independent transcriptional activation function (AF-1); a centrally located zinc-finger DNA-binding domain (DBD); and a C-terminal ligand-binding domain (LBD) that contains ligand-dependent AF-2 (Chandra et al, 2008). The DBD and LBD are well structured and connected via a flexible linker or ‘hinge’ region. NR-interacting proteins include transcriptional coregulators that enzymatically regulate post-translational modification (PTM) of histones and associated proteins (Metivier