Cis or trans: a puzzle of Parkin activation mechanism

The PARK2 gene, which encodes the E3 ubiquitin ligase Parkin, and the PARK6 gene, encoding phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), are frequently mutated in patients with Parkinson's disease (PD). Parkin is normally maintained in an autoinhibited conformation, and its activation is triggered by PINK1-mediated phosphorylation of both ubiquitin or NEDD8 and Parkin's ubiquitin-like (Ubl) domain. This review provides a comprehensive overview of the models proposed over the past decade to explain Parkin's autoinhibition and activation. We summarize key structural and biophysical studies that have progressively uncovered the molecular basis of Parkin activation, tracing the evolution of these insights. This review concludes by discussing the intriguing and still unresolved question of whether Parkin activation occurs through a cis or trans mechanism and outlines future directions for research aimed at understanding these pathways.