Monogenetic, familial forms of Parkinson's disease (PD) only account for 5–10% of the total number of PD cases, but analysis of the genes involved therein is invaluable to understanding PD-associated neurodegenerative signaling. One such gene, parkin, encodes a 465 amino acid E3 ubiquitin ligase. Of late, there has been considerable interest in the role of parkin signaling in PD and in identifying its putative substrates, as well as the elucidation of the mechanisms through which parkin itself is activated. Its dysfunction underlies both inherited and idiopathic PD-associated neurodegeneration. Here, we review recent literature that provides a model of activation of parkin in the setting of mitochondrial damage that involves PINK1 (PTEN-induced kinase-1) and phosphoubiquitin. We note that neuronal parkin is primarily a cytosolic protein (with various non-mitochondrial functions), and discuss potential cytosolic parkin activation mechanisms.
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Multiple protein sequence alignment of the E3 ubiquitin ligase RNF52 from the yeasts (Schizosaccharomyces pombe and Saccharomyces cerevisiae), dimorphic fungus (Candida albicans), thale cress (Arabidopsis thaliana), roundworm (Caenorhabditis elegans), fruit fly (Drosophila melanogaster), zebrafish (Danio rerio), African clawed frog (Xenopus laevis), chicken (Gallus gallus), American alligator (Alligator mississippiensis), human, and mouse (Mus musclus). In this issue of the Biochemical Journal, Shoji et al. report on the role of BRAP, the human form of RNF52, in the oligomeric ubiquitylation process; for details see pages 3207–3226.
Activation mechanisms of the E3 ubiquitin ligase parkin Available to Purchase
Nikhil Panicker, Valina L. Dawson, Ted M. Dawson; Activation mechanisms of the E3 ubiquitin ligase parkin. Biochem J 15 September 2017; 474 (18): 3075–3086. doi: https://doi.org/10.1042/BCJ20170476
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