The E3 ubiquitin protein ligase parkin (PRKN) translocates to the mitochondrial outer membrane (MOM) of damaged mitochondria through a PINK1-dependent mechanism (Matsuda N et al., 2010; Narendra DP et al., 2010; VivesBauza C et al., 2010). PINK1 phosphorylates the ubiquitin-like (UBL) domain of PRKN at the S65 residue (Kondapalli C et al., 2012; Ordureau A et al., 2015; Kazlauskaite A et al., 2015; Gladkova C et al., 2018; Sauvé V et al., 2018). This process is facilitated by the PINK1-mediated phosphorylation of ubiquitin (Ub) moieties on the MOM proteins (Kane LA et al., 2014; Koyano F et al., 2014; ShibaFukushima K et al., 2014; Ordureau A et al., 2015; Kazlauskaite A et al., 2014; Zittlau K et al., 2022). Specifically, PRKN binds to phosphorylated Ub moieties (Kazlauskaite A et al., 2015) and this binding induces allosteric changes that disrupt the inhibitory interdomain interaction between the RING1 domain and the UBL domain of PRKN (Kumar A et al., 2015, 2017). The released UBL of PRKN is phosphorylated at S65 by PINK1 (Kazlauskaite A et al., 2015; Sauvé V et al., 2015) inducing a conformational change in PRKN that enhances its E3 Ub protein ligase activity (Iguchi M et al., 2013; Kondapalli C et al., 2012; Caulfield TR et al., 2014; Kazlauskaite A et al., 2015; Ordureau A et al., 2015; Aguirre JD et al., 2017; Tang MY et al., 2017; Gladkova C et al., 2018; Sauvé V et al., 2018). The conformational change is suppressed in the basal state via autoinhibited conformation (Trempe JF et al., 2013; Kumar A et al., 2015, 2017; Tang MY et al., 2017). Activated PRKN catalyzes the attachment of monoUb and/or polyUb chains to various mitochondrial proteins, marking them either for degradation via the proteasome or promoting selective removal of damaged organelles through autophagy (mitophagy).
In this Reactome event, PINK1 phosphorylates PRKN at S65.
