A molecular simulation study of the clinical G409V mutant in PINK1 associated with early-onset Parkinson's disease

Abstract

The serine/threonine kinase PINK1 is responsible for phosphorylating a ubiquitin (Ub)-like domain in an E3 Ub ligase Parkin protein and a Parkin-bound Ub. PINK1 works as a mitochondrial quality control by phosphorylating and activating the E3 ubiquitin ligase Parkin. Recent medicinal study has reported that mutations of Parkin and PINK1 cause defects in mitophagy and induce early-onset Parkinson's disease (EOPD). In this study, we conducted molecular dynamics simulations to investigate the structural discrepancy caused by a clinical G409V mutation in PINK1 kinase domain's A-loop. The Ub phosphorylation begins with PINK1 D362 deprotonating the hydroxyl group of the substrate Ub's S65′ and PINK1's A-loop is responsible for coordinating S65′. On contrary to G409 offering structural plasticity, the replaced, bulky V409 interferes with the alignment of D362-S65′, seriously hampering Ub phosphorylation, leading to the accumulation of damaged mitochondria, and ultimately EOPD. In this study, we predicted the hPINK1WT-UbWT binding mode and detected the structural impact brought by G409V replacement. It is expected the concluded remarks to be beneficial for developing cures to alleviate structural interference and restore PINK1 function.