Prostaglandin A2 Interacts with Nurr1 and Ameliorates Behavioral Deficits in Parkinson’s Disease Fly Model
The orphan nuclear receptor Nurr1 is critical for the development, maintenance, and protection of midbrain dopaminergic neurons. Recently, we demonstrated that prostaglandins E1 (PGE1) and PGA1 directly bind to the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional activation fun...
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Published in | Neuromolecular medicine Vol. 24; no. 4; pp. 469 - 478 |
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Main Authors | , , , , , , , , |
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Language | English |
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01.12.2022
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Abstract | The orphan nuclear receptor Nurr1 is critical for the development, maintenance, and protection of midbrain dopaminergic neurons. Recently, we demonstrated that prostaglandins E1 (PGE1) and PGA1 directly bind to the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional activation function. In this direction, here we report the transcriptional activation of Nurr1 by PGA2, a dehydrated metabolite of PGE2, through physical binding ably supported by NMR titration and crystal structure. The co-crystal structure of Nurr1-LBD bound to PGA2 revealed the covalent coupling of PGA2 with Nurr1-LBD through Cys566. PGA2 binding also induces a 21° shift of the activation function 2 (AF-2) helix H12 away from the protein core, similar to that observed in the Nurr1-LBD-PGA1 complex. We also show that PGA2 can rescue the locomotor deficits and neuronal degeneration in LRRK2 G2019S transgenic fly models. |
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AbstractList | The orphan nuclear receptor Nurr1 is critical for the development, maintenance, and protection of midbrain dopaminergic neurons. Recently, we demonstrated that prostaglandins E1 (PGE1) and PGA1 directly bind to the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional activation function. In this direction, here we report the transcriptional activation of Nurr1 by PGA2, a dehydrated metabolite of PGE2, through physical binding ably supported by NMR titration and crystal structure. The co-crystal structure of Nurr1-LBD bound to PGA2 revealed the covalent coupling of PGA2 with Nurr1-LBD through Cys566. PGA2 binding also induces a 21° shift of the activation function 2 (AF-2) helix H12 away from the protein core, similar to that observed in the Nurr1-LBD-PGA1 complex. We also show that PGA2 can rescue the locomotor deficits and neuronal degeneration in LRRK2 G2019S transgenic fly models. |
Author | Yoon, Ho Sup Toh, Hui Ting Yoo, Jun Yeob Lim, Kah-Leong Ye, Hong Wang, Ziyin Parnaik, Tanvi Basil, Adeline Henry Rajan, Sreekanth |
Author_xml | – sequence: 1 givenname: Sreekanth orcidid: 0000-0003-4453-3936 surname: Rajan fullname: Rajan, Sreekanth email: srajan@ntu.edu.sg organization: School of Biological Sciences, Nanyang Technological University – sequence: 2 givenname: Hui Ting surname: Toh fullname: Toh, Hui Ting organization: School of Biological Sciences, Nanyang Technological University – sequence: 3 givenname: Hong surname: Ye fullname: Ye, Hong organization: School of Biological Sciences, Nanyang Technological University – sequence: 4 givenname: Ziyin surname: Wang fullname: Wang, Ziyin organization: Neurodegeneration Research Laboratory, National Neuroscience Institute – sequence: 5 givenname: Adeline Henry surname: Basil fullname: Basil, Adeline Henry organization: Neurodegeneration Research Laboratory, National Neuroscience Institute – sequence: 6 givenname: Tanvi surname: Parnaik fullname: Parnaik, Tanvi organization: School of Biological Sciences, Nanyang Technological University – sequence: 7 givenname: Jun Yeob surname: Yoo fullname: Yoo, Jun Yeob organization: School of Biological Sciences, Nanyang Technological University – sequence: 8 givenname: Kah-Leong surname: Lim fullname: Lim, Kah-Leong organization: Neurodegeneration Research Laboratory, National Neuroscience Institute, Lee Kong Chian School of Medicine, Nanyang Technological University – sequence: 9 givenname: Ho Sup surname: Yoon fullname: Yoon, Ho Sup email: hsyoon@ntu.edu.sg organization: School of Biological Sciences, Nanyang Technological University |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/35482177$$D View this record in MEDLINE/PubMed |
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CitedBy_id | crossref_primary_10_3389_fphar_2022_981490 crossref_primary_10_1248_bpb_b23_00600 crossref_primary_10_1016_j_ejmech_2023_115869 crossref_primary_10_3390_ijms241512280 crossref_primary_10_3390_ijms232416184 |
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Keywords | NR4A2 Nuclear receptor Parkinson's disease LRRK2 Drosophila Nurr1 Prostaglandin A2 |
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SubjectTerms | Biomedical and Life Sciences Biomedicine Crystal structure Degeneration Dopamine Dopamine receptors Internal Medicine Kinases Ligands LRRK2 protein Medicine Mesencephalon Movement disorders Neurodegeneration Neurodegenerative diseases Neurology Neurosciences NMR Nuclear magnetic resonance Nuclear receptors Nurr1 protein Original Paper Parkinson's disease Plasmids Prostaglandin E2 Prostaglandins Proteins Titration Transcription activation |
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Title | Prostaglandin A2 Interacts with Nurr1 and Ameliorates Behavioral Deficits in Parkinson’s Disease Fly Model |
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