1 research outputs found
Regulation of the ubiquitin RING E3 ligase Parkin
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