PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function
| Autor: | Chun-Hyung Kim, Hye Min Park, Xue-Wei Liu, Choong Hwan Lee, Bin Song, Sungwhan F. Oh, CongBao Kang, Sreekanth Rajan, Geraldine W.Y. Goh, Gregory A. Petsko, Aida Serra, Jeha Jeon, Hong Ye, Yongwoo Jang, Serap Beldar, Kah-Leong Lim, Woori Kim, Jun Yeob Yoo, Melissa Feitosa, Ho Sup Yoon, Dabin Hwang, Hui Ting Toh, Yeahan Kim, Kwang-Soo Kim, Julien Lescar |
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| Přispěvatelé: | School of Biological Sciences, Interdisciplinary Graduate School (IGS), School of Physical and Mathematical Sciences, Lee Kong Chian School of Medicine (LKCMedicine), National Neuroscience Institute, Nanyang Institute of Technology in Health and Medicine, NTU Institute of Structural Biology |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Transcription Genetic Dopamine Metabolite Crystallography X-Ray Ligands Neuroprotection Article Midbrain Mice 03 medical and health sciences chemistry.chemical_compound Cell Line Tumor Nuclear Receptor Subfamily 4 Group A Member 2 Chemistry [Science] Animals Humans Alprostadil Prostaglandin E1 Molecular Biology Gene 030304 developmental biology Neurons Source Data Mice Inbred BALB C Prostaglandins A 0303 health sciences Transcriptional activity Extended Data 030302 biochemistry & molecular biology Dopaminergic Cell Biology Rats Cell biology Mice Inbred C57BL Neuroprotective Agents chemistry Function (biology) Protein Binding Signal Transduction |
| Zdroj: | Nat Chem Biol |
| Popis: | The orphan nuclear receptor Nurr1 is critical for the development, maintenance and protection of midbrain dopaminergic (mDA) neurons. Here we show that prostaglandin E1 (PGE1) and its dehydrated metabolite, PGA1, directly interact with the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional function. We also report the crystallographic structure of Nurr1-LBD bound to PGA1 at 2.05 Å resolution. PGA1 couples covalently to Nurr1-LBD by forming a Michael adduct with Cys566, and induces notable conformational changes, including a 21° shift of the activation function-2 helix (H12) away from the protein core. Furthermore, PGE1/PGA1 exhibit neuroprotective effects in a Nurr1-dependent manner, prominently enhance expression of Nurr1 target genes in mDA neurons and improve motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse models of Parkinson's disease. Based on these results, we propose that PGE1/PGA1 represent native ligands of Nurr1 and can exert neuroprotective effects on mDA neurons, via activation of Nurr1's transcriptional function. Ministry of Education (MOE) National Medical Research Council (NMRC) National Research Foundation (NRF) This work was supported by NIH grant nos. NS070577 and NS084869 (to K.-S.K.), NRF-2018M3A9B5023055 grant (to C.-H.K.), Ministry of Education Singapore AcRF Tier 2 Grant (no. ARC55/16) and Tang Tieng See Advancement Fund (to H.S.Y.), and National Medical Research Council, Singapore (grant no. TCR/013-NNI/2014; to K.L.L. and H.S.Y.). |
| Databáze: | OpenAIRE |
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