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

Nature Communications
Wei HuangSichun Yang

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.

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Citations

Jul 6, 2019·Journal of Synchrotron Radiation·Awuri AsuruJen Bohon
Mar 30, 2020·Proceedings of the National Academy of Sciences of the United States of America·Elizabeth V WasmuthCharles L Sawyers
Mar 27, 2020·OncoTargets and Therapy·Yanfang LiuJing Yao
Dec 12, 2020·Computational and Structural Biotechnology Journal·Tareq HameduhZbynek Heger
Jan 28, 2021·Cancers·Aditi S KhatpeHarikrishna Nakshatri
Feb 9, 2021·Frontiers in Cell and Developmental Biology·Muhammad IdreesIl-Keun Kong
Feb 24, 2020·Journal of Molecular Biology·Mark R ChanceJanna Kiselar
Aug 14, 2020·Cell Chemical Biology·Julie M Garlick, Anna K Mapp
Feb 1, 2019·Molecular and Cellular Endocrinology·Helder Veras Ribeiro FilhoAna Carolina Migliorini Figueira

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Methods Mentioned

BETA
footprinting
X-ray
size exclusion chromatography
transfection
fluorescence assay
gel filtration
Assay
surface plasmon resonance
chip

Software Mentioned

CRYSOL
pro
MassMatrix
SAXS
Jackal
iSPOT
fast
Amber16
antechamber

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