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A metastable contact and structural disorder in the estrogen receptor transactivation domain

By Yi Peng, Shufen Cao, Janna Kiselar, Xiangzhu Xiao, Zhanwen Du, An Hsien, Soobin Ko, Yinghua Chen, Prashansa Agrawal, Wenwei Zheng, Wuxian Shi, Wei Jiang, Lin Yang, Mark Chance, Witold K. Surewicz, Matthias Buck, Sichun Yang

Posted 28 May 2018
bioRxiv DOI: 10.1101/332205 (published DOI: 10.1016/j.str.2018.10.026)

The N-terminal transactivation domain (NTD) of estrogen receptor alpha, a well-known member of the family of intrinsically disordered proteins (IDPs), mediates the receptor's transactivation function to regulate gene expression. However, an accurate molecular dissection of NTD's structure-function relationships remains elusive. Here, using small-angle X-ray scattering (SAXS), nuclear magnetic resonance, circular dichroism, and hydrogen exchange mass spectrometry, we show that NTD adopts an unexpectedly compact, mostly disordered conformation that undergoes structural expansion upon chemical denaturation. By combining SAXS and hydroxyl radical footprinting measurements, we derive ensemble-structures that represent the natively compact and disordered NTD. The resulting contact map for the ensemble reveals that the NTD features metastable regional and long-range contacts, including specific interactions between residues I33 and S118 that pervade the ensemble. Mutation at S118, a known regulatory site via phosphorylation, promotes conformational changes and increases coactivator binding, confirming its important structural contributions. These findings extend our understanding of IDPs' structure and function, and how specific metastable and/or transient structural interactions within an IDP can mediate critical regulatory functions of disordered proteins.

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