Tumor Susceptibility Gene 101 Regulates the Glucocorticoid Receptor through Disorder-Mediated Allostery

Tumor susceptibility
gene 101 (TSG101) is involved in endosomal
maturation and has been implicated in the transcriptional regulation
of several steroid hormone receptors, although a detailed characterization
of such regulation has yet to be conducted. Here we directly measure
binding of TSG101 to one steroid hormone receptor, the glucocorticoid
receptor (GR). Using biophysical and cellular assays, we show that
the coiled-coil domain of TSG101 (1) binds and folds the disordered
N-terminal domain of the GR, (2) upon binding improves the DNA binding
of the GR in vitro, and (3) enhances the transcriptional activity
of the GR in vivo. Our findings suggest that TSG101 is a bona fide
transcriptional co-regulator of the GR and reveal how the underlying
thermodynamics affect the function of the GR.