GR dimerization and the impact of GR dimerization on GR protein stability and half-life
Date
2019-07-17
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Frontiers Media
Abstract
Pharmacologically, glucocorticoids, which mediate their effects via the glucocorticoid
receptor (GR), are a most effective therapy for inflammatory diseases despite the fact
that chronic use causes side-effects and acquired GC resistance. The design of drugs
with fewer side-effects and less potential for the development of resistance is therefore
considered crucial for improved therapy. Dimerization of the GR is an integral step
in glucocorticoid signaling and has been identified as a possible molecular site to
target for drug development of anti-inflammatory drugs with an improved therapeutic
index. Most of the current understanding regarding the role of GR dimerization in GC
signaling derives for dimerization deficient mutants, although the role of ligands biased
toward monomerization has also been described. Even though designing for loss of
dimerization hasmostly been applied for reduction of side-effect profile, designing for loss
of dimerization may also be a fruitful strategy for the development of GC drugs with less
potential to develop GC resistance. GC-induced resistance affects up to 30% of users
and is due to a reduction in the GR functional pool. Several molecular mechanisms of
GC-mediated reductions in GR pool have been described, one of which is the autologous
down-regulation of GR density by the ubiquitin-proteasome-system (UPS). Loss of GR
dimerization prevents autologous down-regulation of the receptor through modulation of
interactions with components of the UPS and post-translational modifications (PTMs),
such as phosphorylation, which prime the GR for degradation. Rational design of
conformationally biased ligands that select for a monomeric GR conformation, which
increases GC sensitivity through improving GR protein stability and increasing half-life,
may be a productive avenue to explore. However, potential drawbacks to this approach
should be considered as well as the advantages and disadvantages in chronic vs. acute
treatment regimes.
Description
CITATION: Louw, A. 2019. GR dimerization and the impact of GR dimerization on GR protein stability and half-life. Frontiers in Immunology, 10:1693, doi:10.3389/fimmu.2019.01693.
The original publication is available at https://www.frontiersin.org
Publication of this article was funded by the Stellenbosch University Open Access Fund
The original publication is available at https://www.frontiersin.org
Publication of this article was funded by the Stellenbosch University Open Access Fund
Keywords
Glucocorticoids -- Receptors -- Dimerization, Acquired glucocorticoid resistance, Glucocorticoids -- Receptors -- Protein stability, Glucocorticoids -- Receptors -- Effect of drugs on
Citation
Louw, A. 2019. GR dimerization and the impact of GR dimerization on GR protein stability and half-life. Frontiers in Immunology, 10:1693, doi:10.3389/fimmu.2019.01693