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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Data Availability
Coordinates and structure factors for Nurr1-LBD – PGA2 complex have been deposited in the Protein Data Bank with accession number 5YD6.
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Acknowledgements
The authors thank the National Synchrotron Radiation Research Center (NSRRC) and their staff at beamline TLS 13B1 for help with data collection. The NSRRC is a national user facility supported by the National Science Council of Taiwan, ROC; the National Research Program Genomic Medicine supports the Synchrotron Radiation Protein Crystallography Facility at NSRRC. We thank Dr. Aida Serra for help with mass spectrometry data analysis.
Funding
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).
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HSY conceived the study. SR, HTT, HY, ZW, AHB, TP, JYY performed the research and analyzed the data. SR, HTT, KLL, and HSY wrote the paper and all the authors reviewed and approved the final manuscript.
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Rajan, S., Toh, H.T., Ye, H. et al. Prostaglandin A2 Interacts with Nurr1 and Ameliorates Behavioral Deficits in Parkinson’s Disease Fly Model. Neuromol Med 24, 469–478 (2022). https://doi.org/10.1007/s12017-022-08712-3
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DOI: https://doi.org/10.1007/s12017-022-08712-3