Abstract
The glucocorticoid receptor (GR), a nuclear receptor and major drug target, has a highly conserved minor splice variant, GRγ, which differs by a single arginine within the DNA binding domain. GRγ, which comprises 10% of all GR transcripts, is constitutively expressed and tightly conserved through mammalian evolution, suggesting an important non-redundant role. However, to date no specific role for GRγ has been reported. We discovered significant differences in subcellular localisation, and nuclear-cytoplasmic shuttling in response to ligand. In addition the GRγ transcriptome and protein interactome was distinct, and with a gene ontology signal for mitochondrial regulation which was confirmed using Seahorse technology. We propose that evolutionary conservation of the single additional arginine in GRγ is driven by a distinct, non-redundant functional profile, including regulation of mitochondrial function.
Highlights
Glucocorticoids (Gc) exert diverse effects on cell fate, energy metabolism, and immune regulation through the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily
The additional arginine in the DNA binding domain (DBD) is highlighted in red, with adjacent amino acids shown in green. (B) Protein
Using data derived from two independent mass spec (M/S) analyses, we identified a total of 868 GR interacting proteins
Summary
Glucocorticoids (Gc) exert diverse effects on cell fate, energy metabolism, and immune regulation through the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily. In its unliganded state GR is predominantly cytoplasmic, sequestered in a multiprotein complex that includes immunophilins and heat shock proteins. The transformed GR is released from the multiprotein complex, rapidly translocates to the nucleus and binds to cis-elements to regulate gene expression. A feature of all nuclear receptors, including GR, is a modular structure comprising an N-terminal modulating domain, a C-terminal ligand binding domain and a central DNA binding domain (DBD). The DBD is critically important for directing sequence specific DNA binding, it lies adjacent to a nuclear localisation signal, and is an important protein interaction surface, coordinating the recruitment of proteins to GR complexes. Modification of the DBD may alter target gene selection, nucleocytoplasmic shuttling and protein-protein interactions. The additional arginine in the DBD is highlighted in red, with adjacent amino acids shown in green. (B) Protein
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