Parkin (PRKN/PARK2)

Parkin, encoded by the PRKN gene (formerly PARK2), is a RING-between-RING E3 ubiquitin ligase that operates at the centre of mitochondrial quality control. In the cytosol it is held in an autoinhibited conformation. When PINK1 accumulates on damaged mitochondria, it phosphorylates ubiquitin and the ubiquitin-like (Ubl) domain of Parkin at Ser65, releasing autoinhibition and recruiting Parkin to the outer mitochondrial membrane. Activated Parkin builds ubiquitin chains, enriched in K6, K11 and K63 linkages, on outer-membrane substrates such as MFN1/2, MIRO and VDAC1. These chains attract autophagy receptors including OPTN, NDP52 and p62, leading to engulfment of the mitochondrion by an autophagosome. Loss-of-function PRKN mutations cause autosomal recessive juvenile parkinsonism, linking impaired mitophagy to neurodegeneration.