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

doi:10.1038/s41467-018-06034-2

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

Journal Article · Thu Aug 30 00:00:00 EDT 2018 · Nature Communications

DOI:https://doi.org/10.1038/s41467-018-06034-2· OSTI ID:1466428

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.;

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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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE; National Inst. of Health (NIH) (United States)

Grant/Contract Number:: AC02-05CH11231; AC02-06CH11357; GM114056; EB009998; UL1TR000439; GM103622

OSTI ID:: 1466428

Alternate ID(s):: OSTI ID: 1477421

Journal Information:: Nature Communications, Journal Name: Nature Communications Vol. 9 Journal Issue: 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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Cited by: 34 works

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

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