E3 ubiquitin-protein ligase parkin
ubiquitin protein ligase activity
The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI.
Inactivating mutations of the gene encoding parkin are responsible for some forms of autosomal recessive juvenile Parkinson disease. Parkin is a ubiquitin ligase that ubiquitinates misfolded proteins targeted for the proteasome-dependent protein degradation pathway. Using the yeast two-hybrid system and co-immunoprecipitation methods, we identified synaptotagmin XI as a protein that interacts with parkin. Parkin binds to the C2A and C2B domains of synaptotagmin XI resulting in the polyubiquitination of synaptotagmin XI. Truncated and missense mutated parkins reduce parkin-sytXI binding affinity and ubiquitination. Parkin-mediated ubiquitination also enhances the turnover of sytXI. In sporadic PD brain sections, sytXI was found in the core of the Lewy bodies. Since synaptotagmin XI is a member of the synaptotagmin family that is well characterized in their importance for vesicle formation and docking, the interaction with this protein suggests a role for parkin in the regulation of the synaptic vesicle pool and in vesicle release. Loss of parkin could thus affect multiple proteins controlling vesicle pools, docking and release and explain the deficits in dopaminergic function seen in patients with parkin mutations.