Anin-silicoapproach to study the molecular interaction of the PINK1 kinase domain with Parkin Ubl domain

Abstract

ABSTRACTParkinson’s Disease (PD) is the second most common neurodegenerative disorder which creates devastating effects on the neurons of the mid brain. PARK2 and PARK6 genes encode the E3 ubiquitin ligase Parkin and serine/threonine protein kinase PINK1 (PTEN-induced kinase 1), respectively. Mutations in these proteins are responsible for majority of the early onset of PD. PINK1 protein along with Parkin are known to participate in the mitochondrial mitophagy pathway which selectively removes damaged mitochondria. Parkin with the help of its intra-domain interactions goes to an autoinhibited inactive state. Parkin ubiquitin activity is suppressed in this condition. Phosphorylation of the Serine65 residue, present in the Ubl domain of Parkin, is required for its ubiquitin ligase activity. PINK1 protein phosphorylates the Serine65 residue after its self-phosphorylation. After activation, Parkin protein ubiquitinates other damaged mitochondrial proteins for their degradation. Therefore, PINK1-Parkin interaction is important for the proper maintenance of the mitochondrial and neuronal fidelity. In this present work, we are trying to find out how the mutations in the PINK1 kinase domain would affect the modes of its interaction with the Ubl domain of Parkin. We used the three dimensional coordinates of the PINK1 and Ubl domain of Parkin from our previous work and selected the mutations P296L and G309D which have the abilities to hamper the said interactions between PINK1 and the Ubl domain of Parkin. We used molecular docking followed by molecular dynamics simulations to study the nature and structural dynamics of the binding interactions. The results from our study could provide an insight into the PINK1 mediated Parkin activation and plausible biochemical mechanism behind the onset of PD.