ArticlePloS one2024
The N-terminal activation function AF-1 domain of ERα interacts directly with the C-terminal AF-2-holding ligand-binding domain to recruit the coactivator proteins.
Article in PloS one, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5 citing papers in PubMed.
- A Novel SXXLF Motif in the FXR N-Terminal Domain Mediates Coregulator and Interdomain Interactions.Chembiochem : a European journal of chemical biology · 2026Article
- A novel SXXLF motif in the FXR N-terminal domain mediates coregulator and interdomain interactions.bioRxiv : the preprint server for biology · 2026Article
- The Immunoregulatory Roles of ERα in Breast Cancer: Mechanisms, Crosstalk, and Therapeutic Insights.Journal of cancer prevention · 2026Review
- Bisphenol BPAF and BPC are agonists for estrogen receptor ERα but antagonists for N-terminal domain-lacking ERα.PloS one · 2026Article
- Multitarget Design of Steroidal Inhibitors Against Hormone-Dependent Breast Cancer: An Integrated In Silico Approach.International journal of molecular sciences · 2025Article
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7 authors.
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Abstract
Cryoelectron microscopy (cryo-EM) clarified the quaternary structure of the DNA complex of coactivator-bound estrogen receptor alpha (ERα), revealing the adjacency of the N-terminal domain (NTD) and C-terminal ligand-binding domain (LBD). ERα-NTD and LBD constitute activation function 1 (AF-1) and activation function 2 (AF-2), respectively. These domains are essential for transcription activation. Their spatial proximity was judged to be essential for ERα to recruit the SRC coactivator proteins. In the present study, we first evaluated untethered free ERα-NTD(AF-1) [residues 1-180] and its-truncated desNTD(AF-1)-ERα [residues 181-595] in a luciferase reporter gene assay. ERα-NTD(AF-1) was completely inactive, whereas desNTD(AF-1)-ERα exhibited 66% activity of wild-type ERα. Surprisingly, ERα-NTD(AF-1) was found to inhibit desNTD(AF-1)-ERα markedly. Therefore, assuming that ERα-NTD(AF-1) must also inhibit wild-type full-length ERα, we co-expressed ERα-NTD(AF-1) and full-length ERα. As expected, ERα-NTD(AF-1) inhibited ERα in a dose-dependent manner, but non-competitively for 17β-estradiol. When their intracellular transport was examined immunocytochemically, ERα-NTD(AF-1) showed a distinct translocation from the cytoplasm to the nucleus, despite being expressed solely in the cytoplasm without full-length ERα. This nuclear translocation was attributable to a direct interaction between ERα-NTD(AF-1) and full-length ERα consisting of the nuclear localization signal. The present results demonstrated that, in full-length ERα, the N-terminally tethered NTD(AF-1) domain collaborates with the C-terminal LBD(AF-2) for coactivator recruitment.
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