Year: 2015
Type: article
Abstract: Mutations in the E3 ubiquitin ligase Parkin or the mitochondrial kinase PINK1 cause autoso-mal recessive forms of Parkinson’s disease [1, 2]. Genetic and cell biological studies have impli-cated PINK1 and Parkin as critical elements in mitophagy, a mitochondrial quality control pathway that involves the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal system [1, 2]. Under basal conditions, PINK1 is processed by mitochondrial proteases and tar-geted for degradation by the UPS [1, 2]. Following persistent mitochondrial damage (e.g., treat-ment with the mitochondrial uncoupling agent CCCP) PINK1 is stabilized and accumulates in an active form on the outer mitochondrial membrane [1, 2]. Although PINK1 activity is essen-tial for the mitochondrial recruitment of cytoplasmic Parkin and for the subsequent ubiquitin-dependent clearance of damaged mitochondria, the mode of Parkin activation and recruitment has been elusive [1, 2]. A series of recent papers indicates that PINK1 initiates mitophagy by a two-pronged mecha-nism involving direct phosphorylation of ubiquitin at serine 65 [3–5] and the ubiquitin-like do-main (UbL) of Parkin, also, at serine 65 [6–8] (Fig. 1A, steps 1–2). Biochemical and structural analyses of Parkin demonstrated that the unique Parkin domain (UPD):Rcat interface (previ-
Source: PLoS Genetics
Authors: Brigit E. Riley, James A. Olzmann
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,043
OpenAlex ID: W2079755405