A Snake Uncoiled: Activation of Parkin, a Ubiquitin Ligase Involved in Parkinson'S Disease

Parkin, an E3 ligase, is held in an inactive conformation in the cytosol until activated by the kinase PINK1 in response to mitochondrial damage. Together PINK1 and parkin control a mitochondrial quality control pathway that leads to autophagy of damaged mitochondria (mitophagy). Inactive parkin has been compared to a coiled snake with its E2-binding and catalytic sites obstructed by interdomain contacts. PINK1 activates parkin through a two-step mechanism involving phosphorylation of ubiquitin and the ubiquitin-like domain of parkin. We have used X-ray crystallography, NMR spectroscoy, and hydrogen-deuterium exchange mass spectrometry (HDX-MS) to characterize the large conformational changes that accompany the uncoiling of parkin. The results rationalize Parkinson's disease mutations and substrate selectivity in the PINK1-parkin pathway.