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 language | English |
|---|---|
| Article number | 3520 |
| Journal | Nature communications |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2018 Dec 1 |
Fingerprint
All Science Journal Classification (ASJC) codes
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
}
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 journal › Article
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 -