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

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 (F-19) nuclear magnetic resonance that mutations near I33 alter F-19 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.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE Office of Science (SC)
OSTI Identifier:
1558666
DOE Contract Number:  
AC02-06CH11357
Resource Type:
Journal Article
Journal Name:
Structures
Additional Journal Information:
Journal Volume: 27; Journal Issue: 2
Country of Publication:
United States
Language:
English

Citation Formats

Peng, Yi, Cao, Shufen, Kiselar, Janna, Xiao, Xiangzhu, Du, Zhanwen, Hsieh, An, Ko, Soobin, Chen, Yinghua, Agrawal, Prashansa, Zheng, Wenwei, Shi, Wuxian, Jiang, Wei, Yang, Lin, Chance, Mark R, Surewicz, Witold K, Buck, Matthias, and Yang, Sichun. A metastable contact and structural disorder in the estrogen receptor transactivation domain. United States: N. p., 2019. Web. doi:10.1016/j.str.2018.10.026.
Peng, Yi, Cao, Shufen, Kiselar, Janna, Xiao, Xiangzhu, Du, Zhanwen, Hsieh, An, Ko, Soobin, Chen, Yinghua, Agrawal, Prashansa, Zheng, Wenwei, Shi, Wuxian, Jiang, Wei, Yang, Lin, Chance, Mark R, Surewicz, Witold K, Buck, Matthias, & Yang, Sichun. A metastable contact and structural disorder in the estrogen receptor transactivation domain. United States. doi:10.1016/j.str.2018.10.026.
Peng, Yi, Cao, Shufen, Kiselar, Janna, Xiao, Xiangzhu, Du, Zhanwen, Hsieh, An, Ko, Soobin, Chen, Yinghua, Agrawal, Prashansa, Zheng, Wenwei, Shi, Wuxian, Jiang, Wei, Yang, Lin, Chance, Mark R, Surewicz, Witold K, Buck, Matthias, and Yang, Sichun. Tue . "A metastable contact and structural disorder in the estrogen receptor transactivation domain". United States. doi:10.1016/j.str.2018.10.026.
@article{osti_1558666,
title = {A metastable contact and structural disorder in the estrogen receptor transactivation domain},
author = {Peng, Yi and Cao, Shufen and Kiselar, Janna and Xiao, Xiangzhu and Du, Zhanwen and Hsieh, An and Ko, Soobin and Chen, Yinghua and Agrawal, Prashansa and Zheng, Wenwei and Shi, Wuxian and Jiang, Wei and Yang, Lin and Chance, Mark R and Surewicz, Witold K and Buck, Matthias and Yang, Sichun},
abstractNote = {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 (F-19) nuclear magnetic resonance that mutations near I33 alter F-19 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.},
doi = {10.1016/j.str.2018.10.026},
journal = {Structures},
number = 2,
volume = 27,
place = {United States},
year = {2019},
month = {2}
}

Works referencing / citing this record:

An intrinsically disordered proteins community for ELIXIR
journal, January 2019