Chaugule, V.K.; (2011) Regulation of the ubiquitin RING E3 ligase Parkin. Doctoral thesis , UCL (University College London).

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Abstract

Post-translational modification of proteins by ubiquitin is a central regulatory process in all eukaryotic cells. Substrate selection and type of modification are events catalyzed by the E3 ligase, a component of the ubiquitin pathway. Several ubiquitin E3 ligases are implicated in cancer and other disease states, underlying the need for mechanistic insight of these enzymes. Parkinson’s disease is a neurodegenerative disorder characterised by the loss of dopaminergic neurons from the substantia nigra, the presence of Lewy Bodies, and pathogenic aggregates rich in ubiquitin. Autosomal Recessive Juvenile Parkinsonism (AR-JP), which is one of the most common familial forms of the disease, is directly linked to mutations in the Parkin gene (PARK2). Parkin is a RING E3 and catalyses a range of ubiquitination events (mono, multi mono, K48- and K63- linked poly) in concert with several E2s on a variety of substrates, including itself. Furthermore, Parkin is capable of binding the 26S proteasome and mediates selective degradation of target substrates. The data presented will demonstrate that the Ubiquitin-like domain (UblD) of Parkin functions to inhibit its auto-ubiquitination via a novel mechanism. Pathogenic Parkin mutations disrupt this inhibition and result in a constitutively active molecule. The inhibition is mediated by an intra-molecular interaction between UblD and the C-terminus of Parkin, and Lysine 48 on UblD participates in this interaction. The study also uncovered unique UblD/Ubiquitin Binding Regions (UBRs) on the C-terminus of Parkin that play a novel role in its RING E3 ligase activity. The observations provide critical mechanistic insights into the myriad functions of Parkin and the underlying basis of Parkinson’s disease.

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