Figure 1.

A revised model for GR quaternary structure dynamics. In the absence of ligand, the monomeric cytoplasmic GR forms a heterocomplex with Hsp90, Hsp70, FKBP51, and other proteins (not shown). (1) Ligand binding (GC) induces a conformational change in the GR that leads to either FKBP51-FKBP52 exchange within the heterocomplex, or the complete dissociation from the complex (2). At least two mechanisms appear to regulate the influx of GR molecules to the nuclear compartment: a microtubule/Hsp90 dependent pathway (3b, microtubule not shown) and a microtubule/Hsp90 independent pathway (3a, 3c).³⁵ Early in vivo studies suggests that GR is a dimer before translocation¹⁵ (3a) but a monomeric population cannot be rule out (3c). Nucleoplasmic GR appears to be mostly dimeric,^3,31,34 with at least two contact surfaces localized in the LBD (shown in green) and the DBD (D-loop, shown in black).³¹ The interaction with specify response elements (GREs) is very dynamic (4), in the order of seconds.⁴² DNA induces an allosteric change in the receptor's DBD domain⁵¹ (D-loop shown in red) which triggers a conformational change in the LBD, allowing the formation of tetramers, either in a head-to-head (5a) or head-to-tail (5b) configuration.³ GR tetramers also exchange dynamically with DNA (6) and, if it is the tetramer the quaternary structure that detaches from DNA, then the dissociation into dimers should occur at a much faster temporal scale (7), to account for the mostly complete population of dimers observed in the nucleoplasm.³ This highly dynamic regulation occurs in the context of a chromatin landscape. We speculate that a head-to-tail configuration (5b) may assist in bridging different points in the genome, thus favoring a looping mechanism between distant regulatory sites.