Regulation of Mitophagy by the Parkin Ubiquitin Ligase and PINK1 Ubiquitin Kinase

Abstract

Familial forms of Parkinson's disease arise from loss of the mitochondrial quality control pathway mediated by PINK1, a protein kinase, and Parkin, an E3 ubiquitin ligase. Together, they regulate the disposal of damaged mitochondria by autophagy (mitophagy). When damaged, mitochondria accumulate PINK1, which phosphorylates ubiquitin to recruit cytosolic Parkin. Normally quiescent due to autoinhibitory interactions, Parkin is activated by both phosphorylation by PINK1 and binding phosphorylated ubiquitin. The molecular mechanisms that activate activate Parkin have been the focus of much speculation. Here, I describe the crystal structure of the active conformation of Parkin that shows phosphorylation of parkin by PINK1 leads to a dramatic conformational change to derepress its E2‐binding and catalytic sites. Using a variety of experimental approaches, the activation pathways mediated by phospho‐ubiquitin binding and Parkin phosphorylation are compared. The study deepens our understanding of the mechanisms of Parkin activation and suggests new approaches for the treatment of Parkinson's disease by activating Parkin with small molecules.