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...
| Main Authors: | , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2022
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| Online Access: | https://hdl.handle.net/10356/162249 |
| _version_ | 1811685376218103808 |
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| author | Rajan, Sreekanth Toh, Hui Ting Ye, Hong Wang, Ziyin Basil, Adeline Henry Parnaik, Tanvi Yoo, Jun Yeob Lim, Kah-Leong Yoon, Ho Sup |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Rajan, Sreekanth Toh, Hui Ting Ye, Hong Wang, Ziyin Basil, Adeline Henry Parnaik, Tanvi Yoo, Jun Yeob Lim, Kah-Leong Yoon, Ho Sup |
| author_sort | Rajan, Sreekanth |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T04:43:32Z |
| format | Journal Article |
| id | ntu-10356/162249 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:43:32Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1622492022-10-11T02:18:21Z Prostaglandin A2 interacts with Nurr1 and ameliorates behavioral deficits in Parkinson's disease fly model Rajan, Sreekanth Toh, Hui Ting Ye, Hong Wang, Ziyin Basil, Adeline Henry Parnaik, Tanvi Yoo, Jun Yeob Lim, Kah-Leong Yoon, Ho Sup Lee Kong Chian School of Medicine (LKCMedicine) School of Biological Sciences Science::Medicine Nuclear Receptor Nurr1 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. Ministry of Education (MOE) Ministry of Health (MOH) This work was supported by the Ministry of Education Singapore AcRF Tier 2 Grant (MOE2016-T2-2-055) (YHS) and Ministry of Health NMRC-LCG Singapore Parkinson’s disease Translational Clinical Programme (MOH-000207) (LKL). 2022-10-11T02:18:21Z 2022-10-11T02:18:21Z 2022 Journal Article Rajan, S., Toh, H. T., Ye, H., Wang, Z., Basil, A. H., Parnaik, T., Yoo, J. Y., Lim, K. & Yoon, H. S. (2022). Prostaglandin A2 interacts with Nurr1 and ameliorates behavioral deficits in Parkinson's disease fly model. Neuromolecular Medicine. https://dx.doi.org/10.1007/s12017-022-08712-3 1535-1084 https://hdl.handle.net/10356/162249 10.1007/s12017-022-08712-3 35482177 2-s2.0-85128968148 en MOE2016-T2-2-055 MOH-000207 Neuromolecular Medicine © 2022 The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. All rights reserved. |
| spellingShingle | Science::Medicine Nuclear Receptor Nurr1 Rajan, Sreekanth Toh, Hui Ting Ye, Hong Wang, Ziyin Basil, Adeline Henry Parnaik, Tanvi Yoo, Jun Yeob Lim, Kah-Leong Yoon, Ho Sup Prostaglandin A2 interacts with Nurr1 and ameliorates behavioral deficits in Parkinson's disease fly model |
| title | Prostaglandin A2 interacts with Nurr1 and ameliorates behavioral deficits in Parkinson's disease fly model |
| title_full | Prostaglandin A2 interacts with Nurr1 and ameliorates behavioral deficits in Parkinson's disease fly model |
| title_fullStr | Prostaglandin A2 interacts with Nurr1 and ameliorates behavioral deficits in Parkinson's disease fly model |
| title_full_unstemmed | Prostaglandin A2 interacts with Nurr1 and ameliorates behavioral deficits in Parkinson's disease fly model |
| title_short | Prostaglandin A2 interacts with Nurr1 and ameliorates behavioral deficits in Parkinson's disease fly model |
| title_sort | prostaglandin a2 interacts with nurr1 and ameliorates behavioral deficits in parkinson s disease fly model |
| topic | Science::Medicine Nuclear Receptor Nurr1 |
| url | https://hdl.handle.net/10356/162249 |
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