Arrestin ‐3 binds parkin and enhances parkin‐dependent mitophagy

E3 ubiquitin ligase parkin induces mitophagy via ubiquitination of mitochondrial proteins. Parkin exists in closed autoinhibited conformation with the catalytic site on RING2 (brown circle) and E2 binding site on RING1 (blue ellipse) occluded. The ligase function of parkin activated following its phosphorylation by PINK1 and the binding of phospho-ubiquitin is further regulated by numerous partners. Arrestin-3 binds RING0 and RING1 domains of parkin, promoting its transition to open active conformation with both catalytic and E2 binding site accessible (yellow circles – phosphates; pUb – phosphorylated ubiquitin). Thus, arrestin-3 facilitates mitophagy by enhancing the activity of parkin and of its mitophagy-defective mutant R275W. AbstractArrestins were discovered for their role in homologous desensitization of G-protein-coupled receptors (GPCRs). Later non-visual arrestins were shown to regulate several signaling pathways. Some of these pathways require arrestin binding to GPCRs, the regulation of others is receptor independent. Here, we demonstrate that arrestin-3 binds the E3 ubiquitin ligase parkin via multiple sites, preferentially interacting with its RING0 domain. Identification of the parkin domains involved suggests that arrestin-3 likely relieves parkin autoinhibition and/or stabilizes the enzymatically active “open” conformation of parkin. Arrestin-3 binding enhances ubiquitination by parkin of the mitochondrial protein mitofusin-1 and facilitates parkin-m...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research