Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains
Abstract
Human estrogen receptor alpha (hERα) is a hormone-responsive nuclear receptor (NR) involved in cell growth and survival that contains both a DNA-binding domain (DBD) and a ligand-binding domain (LBD). Functionally relevant inter-domain interactions between the DBD and LBD have been observed in several other NRs, but for hERα, the detailed structural architecture of the complex is unknown. By utilizing integrated complementary techniques of small-angle X-ray scattering, hydroxyl radical protein footprinting and computational modeling, here we report an asymmetric L-shaped “boot” structure of the multidomain hERα and identify the specific sites on each domain at the domain interface involved in DBD–LBD interactions. We demonstrate the functional role of the proposed DBD–LBD domain interface through site-specific mutagenesis altering the hERα interfacial structure and allosteric signaling. The L-shaped structure of hERα is a distinctive DBD–LBD organization of NR complexes and more importantly, reveals a signaling mechanism mediated by inter-domain crosstalk that regulates this receptor’s allosteric function.
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE; National Inst. of Health (NIH) (United States)
- OSTI Identifier:
- 1466428
- Alternate Identifier(s):
- OSTI ID: 1477421
- Grant/Contract Number:
- AC02-05CH11231; AC02-06CH11357; GM114056; EB009998; UL1TR000439; GM103622
- Resource Type:
- Published Article
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Name: Nature Communications Journal Volume: 9 Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United Kingdom
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; computational biophysics; nuclear receptors; SAXS
Citation Formats
Huang, Wei, Peng, Yi, Kiselar, Janna, Zhao, Xuan, Albaqami, Aljawharah, Mendez, Daniel, Chen, Yinghua, Chakravarthy, Srinivas, Gupta, Sayan, Ralston, Corie, Kao, Hung-Ying, Chance, Mark R., and Yang, Sichun. Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains. United Kingdom: N. p., 2018.
Web. doi:10.1038/s41467-018-06034-2.
Huang, Wei, Peng, Yi, Kiselar, Janna, Zhao, Xuan, Albaqami, Aljawharah, Mendez, Daniel, Chen, Yinghua, Chakravarthy, Srinivas, Gupta, Sayan, Ralston, Corie, Kao, Hung-Ying, Chance, Mark R., & Yang, Sichun. Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains. United Kingdom. https://doi.org/10.1038/s41467-018-06034-2
Huang, Wei, Peng, Yi, Kiselar, Janna, Zhao, Xuan, Albaqami, Aljawharah, Mendez, Daniel, Chen, Yinghua, Chakravarthy, Srinivas, Gupta, Sayan, Ralston, Corie, Kao, Hung-Ying, Chance, Mark R., and Yang, Sichun. Thu .
"Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains". United Kingdom. https://doi.org/10.1038/s41467-018-06034-2.
@article{osti_1466428,
title = {Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains},
author = {Huang, Wei and Peng, Yi and Kiselar, Janna and Zhao, Xuan and Albaqami, Aljawharah and Mendez, Daniel and Chen, Yinghua and Chakravarthy, Srinivas and Gupta, Sayan and Ralston, Corie and Kao, Hung-Ying and Chance, Mark R. and Yang, Sichun},
abstractNote = {Human estrogen receptor alpha (hERα) is a hormone-responsive nuclear receptor (NR) involved in cell growth and survival that contains both a DNA-binding domain (DBD) and a ligand-binding domain (LBD). Functionally relevant inter-domain interactions between the DBD and LBD have been observed in several other NRs, but for hERα, the detailed structural architecture of the complex is unknown. By utilizing integrated complementary techniques of small-angle X-ray scattering, hydroxyl radical protein footprinting and computational modeling, here we report an asymmetric L-shaped “boot” structure of the multidomain hERα and identify the specific sites on each domain at the domain interface involved in DBD–LBD interactions. We demonstrate the functional role of the proposed DBD–LBD domain interface through site-specific mutagenesis altering the hERα interfacial structure and allosteric signaling. The L-shaped structure of hERα is a distinctive DBD–LBD organization of NR complexes and more importantly, reveals a signaling mechanism mediated by inter-domain crosstalk that regulates this receptor’s allosteric function.},
doi = {10.1038/s41467-018-06034-2},
journal = {Nature Communications},
number = 1,
volume = 9,
place = {United Kingdom},
year = {Thu Aug 30 00:00:00 EDT 2018},
month = {Thu Aug 30 00:00:00 EDT 2018}
}
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https://doi.org/10.1038/s41467-018-06034-2
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