Tumor susceptibility gene-101 regulates 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 (SHRs), although a detailed characterization of such regulation has yet to be conducted. Here we directly measure binding of TSG101 to one SHR, 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 (NTD) of GR, 2) upon binding, improves DNA-binding of GR in vitro , and 3) enhances the transcriptional activity of GR in vivo . Our findings suggest that TSG101 is a bona fide transcriptional co-regulator of GR.