PINK1 phosphorylates PRKN at S65

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). <p>In this Reactome event, PINK1 phosphorylates PRKN at S65.

E3泛素蛋白连接酶parkin（PRKN）通过PINK1依赖性机制转位至受损线粒体外膜（MOM）（Matsuda N 等，2010；Narendra DP 等，2010；VivesBauza C 等，2010）。PINK1在PRKN的S65残基（Kondapalli C 等，2012；Ordureau A 等，2015；Kazlauskaite A 等，2015；Gladkova C 等，2018；Sauvé V 等，2018）上磷酸化其泛素样（UBL）结构域。此过程得益于PINK1介导的线粒体外膜蛋白上泛素（Ub）残基的磷酸化（Kane LA 等，2014；Koyano F 等，2014；ShibaFukushima K 等，2014；Ordureau A 等，2015；Kazlauskaite A 等，2014；Zittlau K 等，2022）。具体而言，PRKN与磷酸化的Ub残基结合（Kazlauskaite A 等，2015），此结合诱导别构变化，破坏PRKN的RING1结构域与UBL结构域之间的抑制性跨结构域相互作用（Kumar A 等，2015，2017）。PRKN释放的UBL在S65处被PINK1磷酸化（Kazlauskaite A 等，2015；Sauvé V 等，2015），诱导PRKN的构象变化，从而增强其E3 Ub蛋白连接酶活性（Iguchi M 等，2013；Kondapalli C 等，2012；Caulfield TR 等，2014；Kazlauskaite A 等，2015；Ordureau A 等，2015；Aguirre JD 等，2017；Tang MY 等，2017；Gladkova C 等，2018；Sauvé V 等，2018）。该构象变化在基础状态下通过自抑制构象得到抑制（Trempe JF 等，2013；Kumar A 等，2015，2017；Tang MY 等，2017）。活化的PRKN催化单泛素化（monoUb）和/或多泛素化（polyUb）链与各种线粒体蛋白的结合，标记它们通过蛋白酶体降解或通过自噬（线粒体自噬）选择性清除受损的细胞器。在此Reactome事件中，PINK1在S65处磷酸化PRKN。