Molecular Insight Of Q126P PINK1 Mutation Parkinson's Disease
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Abstract
Innate Gene alterations affecting PARK2 and PARK6 are mostly responsible for Parkinson's disease. These genes encode the protein kinase PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. Cooperation between Parkin and PINK1 regulates the mitophagy pathway, which recycles damaged mitochondria following oxidative stress. The E3 ubiquitin ligase Parkin belongs to the RBR family. Parkin protein's C terminal edge is home to the IBR domain. The IBR domain maintains the shape and adjustability of RING domains and displays zinc ion-dependent folding, having two zinc-binding sites. Therefore, a parkin protein mutation in a zinc-binding site may result in inappropriate folding, which ultimately impairs the structure as well as function of the protein. Parkin that has been phosphorylated has worse autoinhibition because the phosphoserine group's altered surface electrostatics interfere with its intramolecular interaction. Early-onset Parkinsonism has been linked to homozygous PINK1 gene variants. A novel homozygous mutation (Q126P) in the PINK1 gene was reported in two German sisters diagnosed with a clinical presentation resembling Parkinsonism. The structural aspect of (Q126P) mutation was studied here. Furthermore, we show how a PINK1 mutation in the Parkinson protein family activates parkin, resulting in the expanded structure needed for E2-ubiquitin binding. All of these results emphasize the significance of the parkin activation process via the PINK1 phosphorylation signal and offer a structural view of the parkin and E3 ubiquitin ligase interaction method.
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