Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains

Wei Huang, Yi Peng, Janna Kiselar, Xuan Zhao, Aljawharah Albaqami, Daniel Mendez, Yinghua Chen, Srinivas Chakravarthy, Sayan Gupta, Corie Ralston, Hung Ying Kao, Mark R. Chance, Sichun Yang

研究成果: Article

7 引文 (Scopus)

摘要

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.

原文English
文章編號3520
期刊Nature communications
9
發行號1
DOIs
出版狀態Published - 2018 十二月 1

指紋

estrogens
Estrogen Receptors
deoxyribonucleic acid
Ligands
ligands
DNA
Cytoplasmic and Nuclear Receptors
Protein Footprinting
Mutagenesis
Cell growth
Crosstalk
Site-Directed Mutagenesis
X ray scattering
Hydroxyl Radical
Cell Survival
X-Rays
human estrogen receptor alpha
mutagenesis
hormones
hydroxyl radicals

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

引用此文

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. 於: Nature communications. 2018 ; 卷 9, 編號 1.
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title = "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.",
author = "Wei Huang and Yi Peng and Janna Kiselar and Xuan Zhao and Aljawharah Albaqami and Daniel Mendez and Yinghua Chen and Srinivas Chakravarthy and Sayan Gupta and Corie Ralston and Kao, {Hung Ying} and Chance, {Mark R.} and Sichun Yang",
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Huang, W, Peng, Y, Kiselar, J, Zhao, X, Albaqami, A, Mendez, D, Chen, Y, Chakravarthy, S, Gupta, S, Ralston, C, Kao, HY, Chance, MR & Yang, S 2018, 'Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains', Nature communications, 卷 9, 編號 1, 3520. https://doi.org/10.1038/s41467-018-06034-2

Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains. / 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.

於: Nature communications, 卷 9, 編號 1, 3520, 01.12.2018.

研究成果: Article

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AU - Huang, Wei

AU - Peng, Yi

AU - Kiselar, Janna

AU - Zhao, Xuan

AU - Albaqami, Aljawharah

AU - Mendez, Daniel

AU - Chen, Yinghua

AU - Chakravarthy, Srinivas

AU - Gupta, Sayan

AU - Ralston, Corie

AU - Kao, Hung Ying

AU - Chance, Mark R.

AU - Yang, Sichun

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

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