A Novel Mechanism of Coactivator Recruitment by the Nurr1 Nuclear Receptor

Nicolas Daffern; Ishwar Radhakrishnan

doi:10.1016/j.jmb.2022.167718

A Novel Mechanism of Coactivator Recruitment by the Nurr1 Nuclear Receptor

Nicolas Daffern, Ishwar Radhakrishnan^*

^*Corresponding author for this work

Molecular Biosciences

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Nuclear receptors constitute one of the largest families of transcription factors that regulate genes in metazoans in response to small molecule ligands. Many receptors harbor two transactivation domains, one at each end of the protein sequence. Whereas the molecular mechanisms of transactivation mediated by the ligand-binding domain at the C-terminus of the protein are generally well established, the mechanism involving the N-terminal domain called activation function 1 (AF1) has remained elusive. Previous studies implicated the AF1 domain as a significant contributor towards the overall transcriptional activity of the NR4A family of nuclear receptors and suggested that the steroid receptor coactivators (SRCs) play an important role in this process. Here we show that a short segment within the AF1 domain of the NR4A receptor Nurr1 can directly engage with the SRC1 PAS-B domain. We also show that this segment forms a helix upon binding to a largely hydrophobic groove on PAS-B, overlapping with the surface engaged by the STAT6 transcription factor, suggesting that this mode of recruitment could be shared by diverse transcription factors including other nuclear receptors.

Original language	English (US)
Article number	167718
Journal	Journal of Molecular Biology
Volume	434
Issue number	16
DOIs	https://doi.org/10.1016/j.jmb.2022.167718
State	Published - Aug 30 2022

Funding

We thank Yongbo Zhang in the IMSERC NMR facility, Ben Owen in the IMSERC MS facility, and Arabela Grigorescu in the Keck Biophysics Facility at Northwestern for technical assistance and advice. This work was supported by a grant from the Sherman Fairchild Foundation to I.R. N.D. was supported by a Molecular Biophysics Training Program traineeship (T32 GM008382). Support for structural biology and biophysics research from the Robert Lurie Comprehensive Cancer Center is gratefully acknowledged. We thank Yongbo Zhang in the IMSERC NMR facility, Ben Owen in the IMSERC MS facility, and Arabela Grigorescu in the Keck Biophysics Facility at Northwestern for technical assistance and advice. This work was supported by a grant from the Sherman Fairchild Foundation to I.R. N.D. was supported by a Molecular Biophysics Training Program traineeship (T32 GM008382). Support for structural biology and biophysics research from the Robert Lurie Comprehensive Cancer Center is gratefully acknowledged.

Keywords

per-ARNT-sim domain
protein-protein interaction
solution NMR spectroscopy
steroid receptor coactivator
transcription regulation

ASJC Scopus subject areas

Molecular Biology
Biophysics
Structural Biology

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title = "A Novel Mechanism of Coactivator Recruitment by the Nurr1 Nuclear Receptor",

abstract = "Nuclear receptors constitute one of the largest families of transcription factors that regulate genes in metazoans in response to small molecule ligands. Many receptors harbor two transactivation domains, one at each end of the protein sequence. Whereas the molecular mechanisms of transactivation mediated by the ligand-binding domain at the C-terminus of the protein are generally well established, the mechanism involving the N-terminal domain called activation function 1 (AF1) has remained elusive. Previous studies implicated the AF1 domain as a significant contributor towards the overall transcriptional activity of the NR4A family of nuclear receptors and suggested that the steroid receptor coactivators (SRCs) play an important role in this process. Here we show that a short segment within the AF1 domain of the NR4A receptor Nurr1 can directly engage with the SRC1 PAS-B domain. We also show that this segment forms a helix upon binding to a largely hydrophobic groove on PAS-B, overlapping with the surface engaged by the STAT6 transcription factor, suggesting that this mode of recruitment could be shared by diverse transcription factors including other nuclear receptors.",

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A Novel Mechanism of Coactivator Recruitment by the Nurr1 Nuclear Receptor

Abstract

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Keywords

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