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 and Sichun Yang ()
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Wei Huang: Case Western Reserve University
Yi Peng: Case Western Reserve University
Janna Kiselar: Case Western Reserve University
Xuan Zhao: Case Western Reserve University
Aljawharah Albaqami: Case Western Reserve University
Daniel Mendez: Case Western Reserve University
Yinghua Chen: Case Western Reserve University
Srinivas Chakravarthy: Argonne National Laboratory
Sayan Gupta: Lawrence Berkeley National Laboratory
Corie Ralston: Lawrence Berkeley National Laboratory
Hung-Ying Kao: Case Western Reserve University
Mark R. Chance: Case Western Reserve University
Sichun Yang: Case Western Reserve University

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06034-2

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