Compact Disorder of Estrogen Receptor

Abstract

The N-terminal Transactivation Domain (NTD) of human estrogen receptor alpha is a molecular driver of breast cancer responsible for its constitutive activation function. The NTD is transcriptionally active—in the absence of activating hormones—via its engagement with coactivator proteins. Clinically, the NTD is emerging as a recurrent driver for hormone-independent growth and endocrine therapy resistance. In particular, the receptor is recently found to be active in late-stage breast cancer, where its C-terminal region responsible for hormone binding/activation is truncated, making current anti-estrogen therapies impervious. Structurally, our recently published data and other literature reports show that the NTD is intrinsically disordered. However, the molecular mechanisms by which the NTD acts via its conformation as a disorder system to influence transcriptional function and to interact with coactivator proteins for biomolecular recognition are not known yet. To fill the knowledge gap, we conduct multi-technique investigations by integrating small-angle X-ray scattering, hydroxyl radical protein footprinting, 19F-NMR spectroscopy, and computational methods. In contrast to binding-induced folding seen for other disordered proteins, this study provides novel insight into this intriguing structural disorder of the NTD—that remains disordered even upon coactivator binding—and will ultimately achieve a fundamental structure-function view of this NTD that drives both endocrine therapy resistance and cancer metastasis.