RESUMEN
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.
Asunto(s)
Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Enfermedad de Parkinson , Prostaglandinas A , Humanos , Ligandos , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Prostaglandinas A/genética , Prostaglandinas A/metabolismo , Animales Modificados Genéticamente , Drosophila , Modelos Animales de EnfermedadRESUMEN
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.