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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Article number3520
JournalNature communications
Volume9
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

Fingerprint

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)

Cite this

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. In: Nature communications. 2018 ; Vol. 9, No. 1.
@article{01c332d774284294a43559137da5c90a,
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",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41467-018-06034-2",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

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, vol. 9, no. 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.

In: Nature communications, Vol. 9, No. 1, 3520, 01.12.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85052645577&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052645577&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-06034-2

DO - 10.1038/s41467-018-06034-2

M3 - Article

C2 - 30166540

AN - SCOPUS:85052645577

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 3520

ER -