Prostaglandin A2 Interacts with Nurr1 and Ameliorates Behavioral Deficits in Parkinson's Disease Fly Model.
Drosophila
LRRK2
NR4A2
Nuclear receptor
Nurr1
Parkinson's disease
Prostaglandin A2
Journal
Neuromolecular medicine
ISSN: 1559-1174
Titre abrégé: Neuromolecular Med
Pays: United States
ID NLM: 101135365
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
received:
14
01
2022
accepted:
09
04
2022
pubmed:
29
4
2022
medline:
26
11
2022
entrez:
28
4
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35482177
doi: 10.1007/s12017-022-08712-3
pii: 10.1007/s12017-022-08712-3
doi:
Substances chimiques
Ligands
0
Nuclear Receptor Subfamily 4, Group A, Member 2
0
prostaglandin A2
K6VT5BDY9E
Prostaglandins A
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
469-478Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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