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  • A Metastable Contact and Structural Disorder in the Estrogen Receptor Transactivation Domain.

A Metastable Contact and Structural Disorder in the Estrogen Receptor Transactivation Domain.

Structure (London, England : 1993) (2018-12-26)
Yi Peng, Shufen Cao, Janna Kiselar, Xiangzhu Xiao, Zhanwen Du, An Hsieh, Soobin Ko, Yinghua Chen, Prashansa Agrawal, Wenwei Zheng, Wuxian Shi, Wei Jiang, Lin Yang, Mark R Chance, Witold K Surewicz, Matthias Buck, Sichun Yang
ABSTRACT

The N-terminal transactivation domain (NTD) of estrogen receptor alpha, a well-known member of the family of intrinsically disordered proteins, mediates the receptor's transactivation function. However, an accurate molecular dissection of NTD's structure-function relationships remains elusive. Here, we show that the NTD adopts a mostly disordered, unexpectedly compact conformation that undergoes structural expansion on chemical denaturation. By combining small-angle X-ray scattering, hydroxyl radical protein footprinting, and computational modeling, we derive the ensemble-structures of the NTD and determine its ensemble-contact map revealing metastable long-range contacts, e.g., between residues I33 and S118. We show that mutation at S118, a known phosphorylation site, promotes conformational changes and increases coactivator binding. We further demonstrate via fluorine-19 (19F) nuclear magnetic resonance that mutations near I33 alter 19F chemical shifts at S118, confirming the proposed I33-S118 contact in the ensemble of structural disorder. These findings extend our understanding of how specific contact metastability mediates critical functions of disordered proteins.

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Roche
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